Oral Pathology; Oral Biology
My major interest is focused on clinical translation of biological mechanisms for wound healing and tissue regeneration. Our group uses cell-molecular biology, biomaterials and biomedical technologies to explore biological regulation and use this information for therapeutics to control favorable clinical outcomes.
My laboratory is broadly focused on investigating microbe-microbe interactions, host-microbe interactions, and patient characteristics that influence disease severity. Our primary disease model is catheter-associated urinary tract infection (CAUTI), one of the most common healthcare-associated infections worldwide. Long-term use of indwelling catheters, which is common for management of certain conditions particularly in aging populations, results in continuous urine colonization by bacteria (bacteriuria) and can lead to infections of the bladder (cystitis), kidneys (pyelonephritis), and bloodstream (bacteremia). My lab uses a combination of basic science and patient-oriented research, with the long-term goals of 1) identifying the uropathogen(s) most likely to cause symptomatic infection and adverse outcomes in patients, 2) utilizing an experimental model of infection to identify key virulence factors of these organisms, and 3) developing inhibitors of the identified virulence factors to reduce colonization and infection severity in vulnerable patient populations. As bacteriuria and CAUTI are frequently polymicrobial, which can influence the progression of the infection and the efficacy of antibiotic therapy, a major emphasis of this work is on understanding the contribution of polymicrobial colonization and microbe-microbe interactions to infection progression. We recently identified the Gram-negative bacterium Proteus mirabilis as the most common cause of CAUTI in a cohort of nursing home residents, including cases of polymicrobial infection. P. mirabilis is well-known for its potent urease enzyme, which produces ammonia from the hydrolysis of urea in urine and leads to high urine pH, precipitation of polyvalent ions, and formation of urinary stones (urolithiasis). We recently determined that P. mirabilis urease activity is enhanced during co-culture with other common uropathogens in vitro and in vivo, contributing to increased tissue damage and bacteremia. Enhanced urease activity appears to be a broad phenomenon, occurring with numerous isolates of P. mirabilis during co-culture with most of the other common uropathogens, including Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Therefore, one project in the lab focuses on defining the underlying mechanism of enhanced urease activity and determining its potential as a therapeutic target. Another focus of the lab is utilizing genome-wide screens to uncover new genes that contribute to pathogenesis during both monomicrobial and polymicrobial infection. We are using transposon insertion-site sequencing (Tn-Seq) to identify the full potential arsenal of P. mirabilis fitness and virulence factors during experimental CAUTI, including core factors that contribute to pathogenicity under all infection conditions tested, and accessory factors that are only required under certain infection conditions.
Synapses are the primary points of communication between cells of the nervous system. Our laboratory is interested in synaptic receptors and ion channels. We study the molecular events that constitute agonist binding, channel activation and receptor desensitization. Our research bridges physiology pharmacology, biochemistry and structural biology, and our experimental approaches include electrophysiology, computational chemistry (MD simulations) and molecular biology. We seek to to understand the molecular operation of receptors and other allosteric membrane proteins in the context of their physiological roles. CONTACT INFORMATION: email@example.com (716) 510-0793
We study the regulation of ion transport in epithelia. We are interested in a sodium channel expressed in many epithelia throughout the body. In the kidneys, this channel and its regulation, modify renal sodium excretion and body sodium balance. We are interested in mechanisms which control channel activity and more specifically, in the mechanism of channel activation from the extracellular space. Our lab is also interested in the translational aspect of channel activation and specifically in the discovery of biomarkers of channel activators. These biomarkers can likely report on channel activation in vivo and in this case, can serve can predictors of human hypertension
Cell growth, differentiation and development; Cytoskeleton and cell motility; Genomics and proteomics; Molecular and Cellular Biology; Molecular Basis of Disease; Gene Expression; Signal Transduction; Cell Cycle
I am a cell biologist and bioengineer, and my primary research focuses on the rapidly growing area of cell mechanics and mechanotransduction: the role that mechanical forces play in regulating cellular function from healthy to diseased phenotypes. (1) Cardiovascular Biology, Mechanics and Disease: Funding source: American Heart Association (7/1/2018–6/30/2021; PI) Cardiovascular disease (CVD) is the main cause of death globally. Arterial stiffness is associated with many CVD. The molecular mechanisms governing arterial stiffening and the phenotypic changes in vascular smooth muscle cells (VSMCs) associated with the stiffening process are key areas in cardiovascular biology, mechanics and disease. Evidence suggests that arterial stiffening can drive aberrant migration and proliferation of VSMCs within the vessel wall. Yet, the underlying mechanisms regulating vascular stiffening and the molecular changes within VSMCs associated with the stiffening process remain unclear. While medications reduce hypertension, none specifically target pathways directly related to arterial stiffness. The overall goal of work in my lab is to address this gap in our understanding by investigating how changes in arterial stiffness affect VSMC function and fundamentally contribute to the progression of CVD. This study also addresses an important concept in vascular tissue remodeling (the interaction between extracellular matrix stiffness and VSMC behavior). Methodologically, my lab use a novel approach to dissect the molecular mechanism in VSMCs: My lab combines methods for manipulating and measuring tissue and cell stiffness using atomic force microscopy and traction force microscopy for simultaneously modulating substrate stiffness and measuring contraction force by culturing cells on a compliant substrate that mimics in vivo mechanical environments of the VSMCs. (2) Smooth Muscle Cell (and Cancer Cell) Heterogeneity: Highly heterogeneous responses of VSMCs to arterial stiffness or CVD make it difficult to dissect underlying molecular mechanisms. To overcome this, my lab integrates Mechanobiology, Vascular Cell Biology, and Machine Learning to manipulate stiffness and assess responses with unique precision. Machine learning is used to deconvolve inter- and intra-cellular heterogeneity and identify specific subcellular traits that correlate with stiffness and VSMC behavior. My lab also applies Machine Learning approaches to identify specific breast cancer cell behaviors that respond to different stiffness conditions. (3) Optogenetics and Biophotonics in Stem Cell Biology: Funding source: National Science Foundation (8/1/2017–7/31/2020; co-PI) Major breakthroughs in the field of genomics, embryonic stem cell biology, optogenetics and biophotonics are enabling the control and monitoring of biological processes through light. Additional research in my laboratory focuses on developing a nanophotonic platform able to activate/inactivate gene expression and, thus, control stem cell differentiation in neuronal cells, by means of light-controlled protein-protein interactions. More specifically, the light-controlled molecular toggle-switch based on Plant Phytochrome B and transcription factor Pif6 will be utilized to control the nuclear fibroblast growth factor receptor-1, which is a master regulator of stem cell differentiation. Open Positions: The Bae lab is currently accepting graduate students through the Pathology Masters program (or other programs) as well as motivated undergraduates. For Graduate Students: I am looking for one or two graduate (MS) students who understand my research interests, have read my previous publications, and have their own (crazy!!!) ideas as to where my research efforts should be directed. All graduate students are required to complete and submit internationally recognized Journal article(s) before graduation from my lab. A Masters thesis should generate at least one first author publication. For Undergraduate Students: I encourage all UB undergraduates (with GPA 3.0 or higher) to get "hands on" experimental training in the sciences. An undergraduate research project tends to be part of a larger whole, but I make sure to include credit for students work in presentations and publications.
The focus of my research is on understanding the comparative neurochemical organization of brainstem and cerebellar structures that mediate balance, posture and movement and analyzing how this organization may vary with development, learning, aging, gender or neurological disease. I am also interested in how these systems have changed over evolution, and am comparing brainstem and cerebellar organization in humans and apes.
Eukaryotic Pathogenesis; Microbial Pathogenesis; Microbiology; Molecular and Cellular Biology
Human African trypanosomiasis (commonly called Sleeping Sickness) is one of the global great neglected diseases, causing ~10,000 cases annually according to most recent estimates (2009). The related veterinary disease of livestock (Nagana) also has significant impact on human economic well being throughout sub-Saharan Africa wherever the insect vector (tsetse flies) are found. Both diseases are caused parasitic protozoa called trypanosomes (Trypanosoma brucei ssp.) Because trypanosomes are eukaryotic cells, organized similarly to every cell in our bodies, treatment of infection is not unlike cancer treatment in that chemotherapy against the parasite has harsh consequences for the patient. However, infection is invariably fatal without intervention, consequently new more specific drugs are desperately needed. In addition, because trypanosomes are an anciently divergent evolutionary lineage, they provide a unique model system for studying basic eukaryotic biology. My laboratory focuses on the cell biology of these protozoa, specifically on intracellular trafficking of lysosomal and cell surface proteins as key aspects of the host:parasite relationship. The trypanosome lifecycle alternates between the mammalian bloodstream and the tsetse midgut, and each stage has a unique protein surface coat that forms the first line of contact with the host. These coat proteins are anchored in membranes by glycosylphosphatidylinositol (GPI) anchors and are essential for survival in each stage. Consequently, correct protein targeting to the cell surface is critical to the success of the parasite. Also, endocytic and lysosomal functions are greatly up-regulated in the pathogenic bloodstream stage for both nutritional and defensive purposes. Using classic and current cell biological and biochemical approaches we work on four distinct areas: 1) GPI-dependent targeting of surface coat proteins; 2) machinery of secretory trafficking; 3) stage-specific lysosomal biogenesis and proteomics; and 4) role of sphingolipids in secretory transport. Our ultimate goal is to define aspects of trypanosomal secretory processes that may provide novel avenues to chemotherapeutic intervention.
My research focus is on the study of the interaction of inflammatory leukocytes and fibroblasts with tumor cells in human lung and ovarian tumor microenvironments by using an immunodeficient tumor xenograft model. This model includes the tumor, the tumor-associated stromal fibroblasts and the inflammatory cells, including lymphocytes. In my lab, I work with a research team of students and postdoctoral fellows to study the immune response of cancer patients to their tumors. Our data indicate that tumor-specific lymphocytes, once present in the tumor microenvironment, become hyporesponsive and fail to attack and kill tumor cells. This hyporesponsiveness is due to an arrest or checkpoint in the T cell receptor (TCR) signaling machinery. Our studies are designed to gain a better understanding of the molecular events that are responsible for signaling arrest. We also aim to determine ways to prevent, or even reverse the TCR signaling arrest, for example, by eliminating or blocking the lipid-mediated disruption of the TCR signaling cascade. Using the tumor xenograft models, we have structurally identified the immunoinhibitory factors present within the tumor ascites fluids and determined the mechanism by which they arrest the TCR signaling. We found that these cells fail to respond to activation signals due to the disruption of the TCR signaling cascade that occurs at, or just proximal to the activation of PLC-γ. An identical TCR signaling arrest also occurs in human T cells found in chronic inflammatory tissues. Using the xenograft models, we established that a local and sustained release of IL-12 into the tumor microenvironment activates the quiescent tumor-associated T cells to produce and secrete IFN-γ, which mobilizes an immune-mediated eradication of the tumor. We recently found that lipids present within the ascites fluids of human ovarian tumor mediate a reversible arrest in the TCR signaling pathway of ovarian tumor-associated T cells. We have now determined that extracellular microvesicles (exosomes) isolated from human ovarian tumors and tumor ascites induce a rapid and reversible arrest in the T cell signaling cascade. The T cell inhibition is causally linked to phosphatidylserine that is expressed on the outer leaflet of the exosome membrane. The target of this arrest is diacylglycerol, and the induced suppression is blocked or reversed by diacylglycerol kinase inhibitors. This suggests a likely mechanism by which the tumor-associated exosomes arrest both CD4+ and CD8+ T cell activation. The ability to eliminate or block/reverse that inhibitory activity of the exosomes represents a potentially viable therapeutic target for enhancing patients’ antitumor response and for preventing the loss of function of CAR-T cells upon entry into the tumor microenviroment. These findings will provide valuable information in designing new immunotherapeutic strategies for patients with advanced cancer.
Addictions; Drug abuse; Behavioral pharmacology; Gene therapy; Molecular and Cellular Biology; Neurobiology; Gene Expression; Neuropharmacology
My laboratory seeks to understand the neurobiology of motivation and how these systems can be "highjacked" by abused substances. Substance abuse and addiction are wide-spread problems that have an enormous economic and emotional toll. Reports indicate that it costs the US upwards to $600 billion a year to deal with the health and criminal consequences and loss of productivity from substance abuse. Despite this, there are few effective treatments to combat this illness. The brain has natural systems responsible for motivating an organism to participate in behaviors that are necessary for survival, such as eating, exercise and reproduction. These same brain regions are highly sensitive to drugs of abuse, including cocaine, heroin and marijuana. My laboratory seeks to understand how these brain regions are affected by exposure to abused drugs, and in particular how the motivation to take drugs is altered by various molecular mediators in the neurons on these regions. The two basic questions we are interested in are 1) how projections from the cortex to the striatum influence drug seeking behaviors, and 2) how neurotransmitter receptors, particularly dopamine and cannbinoid receptors in these regions influence drug seeking. Our technical approaches include a number of basic behavioral models including measurements of locomotor activity, catalepsy, conditioned place preference and drug self-administration. In order to probe the circuitry of these brain regions, we use a number of advanced molecular techniques to activate and inactivate neuronal populations including optogenetics and artificial receptors. We probe the molecular pathways within the neurons by over expressing genes or knocking down expression using RNA interference. Gene delivery is accomplished using recombinant adeno-associated virus (rAAV) and several projects in the laboratory focus on improving this approach and exploring potential gene therapy applications for these vectors. The ultimate goal is to understand the basic neurobiology and molecular biology of addiction in order to develop more effective treatments for addiction.
Apoptosis and cell death; Bioinformatics; Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Neurobiology; Regulation of metabolism
My laboratory studies the cell-autonomous and non-cell-autonomous mechanisms of axon degeneration, a process akin to programmed cell death. In other words, we are attempting to elucidate what causes axon breakdown from within neurons and which external (glial) events trigger axon loss. Degeneration of axons is a hallmark in many neurodegenerative conditions, including those associated with abnormal glia. We have great hope that understanding why and how axons degenerate may lead to more efficient neuroprotective therapies tailored specifically to support axons and their surrounding glia. Axons are the longest cellular projections of neurons relaying electrical and biochemical signals in nerves and white-matter tracts of the nervous system. As such, they are critical for neuronal wiring and transport of neuronal maintenance signals. Because of their incredible length and energetic demand (human motor neurons can be one meter long), however, axons are very vulnerable and at continuous risk of damage. Axons do not exist in isolation but are inextricably and intimately associated with their enwrapping glia (Schwann cells and oligodendrocytes) to form a unique axon-glia unit. The most relevant neurological symptoms in a number of debilitating neurodegenerative conditions are due to compromised axon integrity. Thus, neuroprotective therapies promoting axon stability have great potential for more effective treatment. Recent studies indicate that axonal degeneration, at least in experimental settings, is an active and highly regulated process akin to programmed cell death (‘axonal auto-destruction’). Moreover, it is increasingly realized that axonal maintenance relies not only on neuron-derived provisions but also on trophic support from their enwrapping glia. The mechanism for this non-cell-autonomous support function remains unknown, but emerging evidence indicates that it is distinct from the glial role in insulating axons with myelin. We are pursuing the intriguing question of whether abolished support by aberrant delivery of metabolites and other trophic factors from glia into axons is mechanistically linked to the induction of axonal auto-destruction. This concept is supported by our recent finding that metabolic dysregulation exclusively in Schwann cells is sufficient to trigger axon breakdown.
Forensic Psychiatry; Geriatric Psychiatry; Neurology; Psychiatry; Multiple Sclerosis; Alzheimer Disease / Memory Disorders; Neurodegenerative disorders; Neuropsychology
I direct two UBMD clinics: an outpatient neuropsychology practice at the Buffalo General Medical Center and an inpatient consultation service at the Erie County Medical Center. In addition, I provide services for patients at the Jacobs Multiple Sclerosis Center and the UB Alzheimer’s Disease and Memory Disorders Center. Our clinical mission is to provide compassionate, state-of-the-art care for patients and families affected by a wide range of neurological and psychiatric disorders. Our top-rate neuropsychological services are based on the integration of neurological, psychiatric and imaging findings and structured to meet the needs of our patients and their caregivers. Our neuropsychology service is dedicated to the teaching mission of UB. We support the departments of neurology and psychiatry as well as the rehabilitation services in the orthopaedic, occupational therapy and physical therapy divisions at our UB-affiliated hospitals. We provide practicum and internship placements for UB Psychology Graduate students. Students, residents and fellows have a rich learning experience with us and see a wide range of diseases such as personality disorder, malingering, depression, head trauma, concussion, multiple sclerosis (MS), stroke, dementia, epilepsy and pervasive developmental disorders. Medical students have the opportunity to work with both children and adults during didactic rounds, and they may choose to focus on the evaluation of either patient population based on their clinical focus. My research mission is to employ behavioral psychometrics to understand how cerebral disease affects personality, cognition, and psychiatric stability. Two memory tests I developed, the Brief Visuospatial Memory Test Revised (BVMTR) and the Hopkins Verbal Learning Test Revised (HVLTR), are widely used in neuropsychology, especially in the areas of multiple sclerosis, head injury, and schizophrenia, and they are included in consensus panel test batteries for athlete concussions in the NHL and NFL. I work to develop new tests in order to understand more about the effect of cerebral injuries and disease. I also focus my research in multiple sclerosis (MS) and have conducted several studies on pharmacological and behavioral treatments for cognitive function in MS patients. I have contributed in noteworthy studies as the lead author on a consensus battery for MS patients (the Minimal Assessment of Cognitive Function in MS), which is a gold standard in the literature, and as a major contributor to the idea that brain atrophy is the primary driver of cognitive impairment in MS, and in particular, deep gray matter atrophy. Other research contributions in MS include [a] personality changes and employment, MS dementia, and associations with clinical outcomes, [b] self-report is not a valid indicator of neuropsychological status in MS, [c] Symbol Digit Modalities Test is a reliable and valid marker for cognitive outcomes in clinical trials.
Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Neurobiology; Pathophysiology; Gene Expression; Signal Transduction
Neuronal firing patterns are highly diverse because neurons regulate a wide variety of different behaviors and physiological functions including cognition and memory. Whether a neuron exhibits regular spiking, burst firing, adaptation or high frequency firing will largely be determined by which specific ion channel genes a neuron chooses to express. I am interested in a class of potassium channels that are sensitive to intracellular sodium. There are two members in this family, known as Slack and Slick, and both channel subunits are expressed in many different types of neurons. I am particularly interested in how these channels contribute to the firing patterns of pain-sensing neurons and neurons of the cerebral cortex. Understanding when, where and how these channels are working should provide important information on sensory and cortical processing and will provide insights on nociception, psychiatric disorders such as schizophrenia and bipolar disorder and neurological diseases such as epilepsy.
Molecular genetics; Protein Function and Structure; DNA Replication, Recombination and Repair; Bacterial Pathogenesis
My associates and I use a combination of biochemical and biophysical approaches to study the molecular basis of stalled DNA replication fork rescue. Our model organism is the well-characterized bacterium Escherichia coli (E. coli), since the majority of the proteins thought to be involved in fork rescue are known. Most of our experimental work is concerned with the function and regulation of the complexes that control fork rescue, with studies focused primarily on the role of the single-strand DNA binding protein (SSB) and several recombination DNA helicases. Comparative studies are also underway using selected components of some medically relevant bacterial organisms. We collaborate with scientists from the National Institutes of Health (NIH) and other research institutions. The team working in my lab consists of undergraduate and graduate students, postdoctoral fellows and a technician. We seek to understand fork rescue utilizing both bulk-phase and single molecule techniques. Typically, studies focus initially on purification and characterization of the various proteins (there are now more than 10 being studied). We study DNA binding, unwinding and the hydrolysis of adenosine triphosphate (ATP) using a combination of modern spectroscopic (both ultraviolet–visible and fluorescence) and equilibrium binding methods. The goal of these initial studies is to understand the range of DNA substrates on which an enzyme can act, as a means to understanding its role in vivo. This is followed by careful single molecule studies using a technique I pioneered that combines optical tweezers, microfluidics and high-resolution fluorescence microscopy. My research team is also pursuing a new area of research targeted at developing small molecule inhibitors. These are aimed at disrupting binding between SSB and the 12-14 proteins comprising the SSB-interactome. As SSB is an essential protein and its binding to interactome partners is required for viability, the goal of these studies is to identify inhibitors that will be further developed into novel antibiotics.
Eukaryotic Pathogenesis; Immunology; Infectious Disease; Microbial Pathogenesis; Microbiology; Molecular Basis of Disease; Signal Transduction; Vision science
Toxoplasma gondii is an obligate intracellular parasite that has the unique ability of infecting most nucleated cells in almost all warm-blooded animals. It is one of the most widespread infections in the world: approximately 50 percent of the world‘s population is infected. Luckily, most infected people are asymptomatic; however, in AIDS patients and other immune-compromised individuals, Toxoplasma causes serious and life-threatening disease. Besides its own medical importance, we study Toxoplasma because it represents an ideal model system to study how other related pathogens cause disease. These include Plasmodium, which is the causative agent of malaria that is responsible for millions of deaths worldwide, and Cryptosporidium, which causes another important secondary infection in AIDS patients. Toxoplasma is a great model system because it can easily be grown in vitro, its genome has been sequenced and it can be genetically manipulated. My research team and I are focused on two different but related questions. First, we want to know how the parasite grows inside of its host cell. One of the important things Toxoplasma must do to grow is hijack host cell pathway and factors. We are using functional genomic assays such as microarrays and genome-wide RNA interference (RNAi) screens to identify these host factors. Identifying them is important because if the parasite cannot use these pathways, the parasite will not grow or cause disease. Thus, these pathways represent novel drug targets. As an example, we discovered that oxygen-regulated transcription factors in the host cell are necessary to support parasite growth. We are currently identifying how these transcription factors function and how the parasite adapts to the various oxygen environments it encounters during its lifecycle. Second, we want to know how Toxoplasma affects the central nervous system and how anti-Toxoplasma immune responses function in the central nervous system. These questions are important because Toxoplasma primarily causes disease in the brain and retina. Our work has revealed that when Toxoplasma actively grows in the brain (a condition known as toxoplasmic encephalitis), it causes a massive reorganization of inhibitory synapses. These changes inhibit GABAergic synaptic transmission and this inhibition is a major factor in the onset of seizures in infected individuals. A second line of research using an ocular infection model has focused on defining how immune responses in the central nervous system are generated by Toxoplasma and then resolved once the infection is under control.
My research is focused on the systematic characterization of genetic and epigenetic factors that contribute to variable drug response in relevant clinical settings. My professional training in clinical biochemistry coupled to my background in cancer pharmacology allow me to perform patient-oriented research through a combination of approaches based on: 1) the analysis of biological samples from selected populations, 2) the use of an array of contemporary experimental platforms, 3) direct translation of laboratory findings into clinical studies in adult and pediatric patients. For example, through pivotal studies in collaboration with Dr. Smita Bhatia and colleagues from the Children’s Oncology group we have demonstrated that functional polymorphisms in genes involved in the pharmacodynamics of anticancer anthracycline drugs contribute to the risk of anthracycline-related cardiotoxicity in long-term survivors of pediatric cancers. Individuals with Down syndrome experience multiple comorbid health problems that necessitate pharmacotherapeutic management with various drugs. We are performing studies to identify molecular determinants associated with the metabolism and disposition of clinically relevant drugs in persons with Down syndrome. New projects in our lab are focused on the characterization of epigenetic determinants that control the variable expression of cellular receptors key for the pharmacological action of monoclonal antibody drugs in humans. Our research in collaboration with colleagues from the Department of Pharmacy Practice is investigating the utilization of clinical pharmacogenetic testing in the State of New York.
Research interests include: 1. Innovations in pedagogy and educational technologies. 2. Drug transport across the blood-brain barrier. Focuses on the mechanisms of drug transport across the blood-brain and blood-cerebrospinal fluid barriers. Nature designed these barriers to restrict and regulate the entry of blood borne substances into brain tissue. Essential nutrients are transported efficiently by carrier proteins expressed by the blood-brain and blood-cerebrospinal fluid barriers. However, these barriers hinder the entry of many drugs, and typically it is only highly lipophilic drugs that gain access to brain tissue via passive diffusion across the barriers. Consequently, many lead drug candidates are disqualified from further development because of poor permeability across the blood-brain barrier. There is much scientific interest in understanding brain transport processes with the goal of identifying methods, which enhance drug delivery across brain barriers. 3. Neuroinflammatory Brain Diseases. Understanding the role of neuroinflammatory processes in the progression of chronic neurodegenerative diseases. Since inflammatory processes are a common feature of many neurological diseases (viz., Alzheimer‘s disease, multiple sclerosis, HIV-1 dementia,cerebral ischemia, brain tumors and meningitis), an enhanced knowledge of inflammatory mediators and their detrimental effects on the centraln ervous system provides opportunities for the design of new pharmaceutical approaches in the management of neurological diseases.
Research in my laboratory focuses on age-associated changes in innate immune responses that render the elderly more susceptible to infections. As the number of individuals above 65 years old is projected to reach 2 billion by 2050, infections in this population poses a serious health and economic burden. A major area of our work is on infections caused by Streptococcus pneumoniae (pneumococcus) that despite the availability of vaccines, remain the leading cause of community-acquired pneumonia in the elderly. Immunosenescence, the age-related decline in immune-cell function, and inflammaging, the age-related increase in basal inflammation, may both contribute to the increased susceptibility of the elderly to life-threatening S. pneumoniae infections such as pneumonia, bacteremia and meningitis. Of particular interest are polymorphonuclear leukocytes (PMN) or neutrophil responses. PMNs are innate immune cells that are key determinants of disease following infection because their initial presence is required to control bacterial numbers, but their persistence in the lungs is detrimental to the host. PMN responses are dysregulated in aging; however, the pathways driving this are not well elucidated. We found that in young hosts, resistance to infection, PMN antibacterial function as well as pulmonary recruitment and resolution following pneumococcal pneumonia is controlled by the extracellular adenosine (EAD) pathway. EAD is produced by the sequential action of two exonucleosidases, CD39 and CD73, and can signal via four known adenosine receptors, that can be pro- or anti-inflammatory. Interestingly, we found that pneumococci can modulate host inflammatory responses by targeting the expression of EAD pathway components. We are using a variety of approaches including in vitro modeling of PMN responses from human donors, mouse models of infection as well as genetic manipulation of bacteria to elucidate the following: 1) How the EAD pathway shapes PMN responses during infection; 2) The role of the EAD pathway in age-driven immune dysregulation; 3) The role of PMNs and the EAD pathway in mounting protective memory responses following vaccination in young and aged hosts; 4) The S. pneumoniae virulence factors required to manipulate the EAD pathway. Elucidating what drives the dysregulated immune responses during aging has the potential of using novel therapies to combat infections in the elderly.
Bioinformatics; Genomics and proteomics; Molecular and Cellular Biology; Molecular genetics; Gene Expression; Transcription and Translation
Instructions controlling cellular functions are contained within DNA that is wrapped and packaged around proteins into chromatin. Chromatin can be modified in response to the environment and these modifications can be passed onto their daughter cells. These modifications act as a cellular memory and are known as epigenetic modifications. Changes in epigenetic modifications are essential players in many disease pathways including: cancer, diabetes, obesity, and autism. Dr. Buck’s research is focused on uncovering how epigenetic changes redirect regulatory proteins and how regulatory proteins read epigenetic modifications. Dr. Buck’s laboratory uses multiple model systems to uncover fundamental biological principles which are subsequently translated to the study of human disease. Epigenomics and Cancer Epigenetic alterations have been associated with cancer-specific expression differences in development of human tumors. The ability to recognize and detect the progression of epigenetic events occurring during tumorigenesis is critical to developing strategies for therapeutic intervention. Key epigenetic alterations, leading to silencing or activation, are associated with changes in nucleosome occupancy. We use chromatin assays (FAIRE-seq, ATAC-seq, MNase-seq, and ChIP-seq) to examine cancer epigenomes from patient samples and cell line models. Transcription factor binding specificity to chromatin. To understand normal developmental processes and disease manifestation and progression we must understand the mechanisms regulating the essential first step of gene activation, transcription factor binding at regulatory regions. Using the developmental transcription factor TP63 we have begun to uncover the rules dictating p63 binding to chromatin. Our findings demonstrated that p63 functions has a pioneer transcription factor that can target it bindings site in closed inaccessible genomic locations. Current in vitro and in vivo studies are beginning to define the how nucleosome position and histone modifications regulate p63 binding. Microbiota in human health Our bodies are populated by a diverse and complex population of thousands of microbes, mostly bacteria, but also viruses, fungi and archaea, termed the human microbiota. This co-inhabiting microbial ecosystem has been associated with various human disease including colon cancer, diabetes, periodontal disease, and others. To understand how the microbiota is affecting human health we are participating in a large epidemiological study examining human oral microbiota samples. We have developed robust and reproducible high-throughput approaches to examine thousands of samples and we are currently defining causual relationships between the microbiota and human health.
Cardiology; Cardiovascular Disease; Clinical Cardiac Electrophysiology; Internal Medicine
An internationally recognized cardiovascular physician-scientist, Dr. Cain is a specialist in abnormal heart rhythms. He is board-certified in internal medicine, cardiovascular diseases and clinical cardiac electrophysiology and pacing. He is a fellow of the American College of Cardiology, the American Heart Association and the Heart Rhythm Society. A former associate editor of Circulation, Cain is a member of the editorial boards of the American Journal of Cardiology, the Journal of Cardiovascular Electrophysiology, Nature Clinical Practice Cardiovascular Medicine and Heart Rhythm. His NIH-supported research has focused on determining the mechanisms of life-threatening heart rhythm abnormalities that occur in heart attacks and other conditions that damage heart muscle cells. This information is being used to better characterize and more accurately localize the abnormal heart tissue responsible for these abnormal heart rhythms and to improve the identification of patients at increased risk for sudden cardiac death.
Bacterial Pathogenesis; Infectious Disease; Microbial Pathogenesis; Microbiology
My research interests focus on bacterial pathogenesis, emphasizing bacterial biofilms, antimicrobial therapies and vaccine antigens. One major area of my research lab is otitis media (OM) or middle ear disease. Approximately 80 percent of children experience one episode of OM while others have recurrent infections. Chronic OM infection causes hearing impairment leading to developmental problems as these children reach school age. My laboratory has concentrated on two major causes of OM, Moraxella catarrhalis and Streptococcus pneumoniae. Our recent work suggests that M. catarrhalis colonization predisposes patients to colonization with S. pneumoniae in polymicrobial biofilms. The goals of this work are to define biofilm-associated factors and to identify signals that induce bacteria to transition from asymptomatic colonizers to pathogenic organisms leading to OM. Our second major research focus is the identification of novel antimicrobial therapies. Chronic OM is likely a biofilm-associated disease and biofilms are highly antibiotic resistant. Antibiotic resistance is a major problem worldwide and new drug development is both time consuming and extremely expensive. We have demonstrated that photodynamic therapy (PDT), an FDA-approved cancer treatment, is also bactericidal against the three major otopathogens. Thus, the goal of this research is to adapt PDT into a clinically effective treatment for chronic OM. Our third research area involves novel antimicrobial treatments for orthopedic/prosthetic infections. Infections after orthopedic intervention, including knee/hip replacements and insertion of prosthetic devices, are devastating to the patient and these infections will likely increase over the next 20 years. This is particularly relevant to the military where improvised explosive devices cause severe extremity injuries requiring amputation. Antibiotic-resistant biofilms are the primary source of these infections. In collaboration with colleagues at UB, we are testing a novel electrical stimulation method for prevention/eradication of biofilm infections on implant materials. The goals of this research are to define the optimal antimicrobial parameters that are broadly effective against multiple pathogens, including Staphylococcus aureus, Acinetobacter baumannii, Staphylococcus epidermidis and Klebsiella pneumoniae. The members of my research team typically include a combination of graduate students, lab technicians and a junior faculty member. In the summer, I usually mentor medical students or undergraduates who are interested in the fundamentals of basic science and translational research focused on microbial pathogenesis.
Cardiology; Cardiovascular Disease; Apoptosis and cell death; Cardiac pharmacology; Gene therapy; Genomics and proteomics; Molecular Basis of Disease; Stem Cells
As a SUNY Distinguished Professor of Medicine, I am responsible for the clinical, teaching and research programs related to adult patients with heart disease. I care for patients at the UBMD Internal Medicine practice group in Amherst, the Gates Vascular Institute (GVI) of Buffalo General Medical Center (BGMC) and the Buffalo VA Medical Center (VAMC). My clinical areas of expertise are in diagnosing and caring for patients with coronary artery disease and heart failure. My research group conducts translational studies directed at advancing our mechanistic understanding of cardiac pathophysiology as well as developing new diagnostic and therapeutic approaches for the management of patients with chronic ischemic heart disease. Our ongoing areas of preclinical investigation apply proteomic approaches to identify intrinsic adaptive responses of the heart to ischemia and studies examining the ability of intracoronary stem cell therapies to stimulate endogenous cardiomyocyte proliferation and improve heart function. We also conduct basic and patient-oriented research to understand how reversible ischemia modifies the cellular composition and sympathetic innervation of the heart to help develop new approaches to identify patients at risk of sudden cardiac arrest from ventricular fibrillation. In addition to my laboratory investigation, I serve as the deputy director of the UB Clinical and Translational Research Center (CTRC) and the director of the UB Translational Imaging Center. The Translational Imaging Center offers researchers opportunities to perform multimodality research imaging using PET molecular imaging, high-field magnetic resonance imaging (MRI) and X-ray computed tomography (CT). Our overall goal is to use advanced cardiac imaging to translate new applications between the bench and bedside in order to identify new imaging biomarkers of pathophysiological processes such as chronic myocardial ischemia and cardiac arrhythmogenesis. I am engaged in the cardiology profession at national and international levels, including as former president of the Association of Professors of Cardiology.
Molecular and Cellular Biology; Neurobiology; Neuropharmacology
The goal of my research is to elucidate the endogenous role of two neuropeptide systems and their potential as therapeutic targets; urotensin II (UII) and neuropeptide S (NPS). Both of these peptides regulate basal ganglia function through G protein-coupled receptor (GPCR) mediated intracellular signals. The basal ganglia are critical in motivated behavior (e.g. food seeking), voluntary movement, and the expression of habits (e.g. compulsions). Basal ganglia dysfunction results in neurological disorders as diverse as Parkinsonism and drug addiction. GPCRs are proven to be amenable to drug development and are targeted by over 30 percent of present day pharmaceuticals. My goal is to exploit the UII and NPS systems to improve the medical treatment of neurological disorders. Currently my lab is pursuing the following: 1) Determine the role of UIIR activation and the UIIR expressing neurons in reward-related behaviors:. Our results support the need for further investigation of the UII-system as a therapeutic target for treating drug abuse disorders. In addition, we are investigating the i) bias-signaling properties of the endogenous UIIR ligands, and ii) the impact of UIIR single-nucleotide polymorphisms on receptor signaling. 2) We designed a toxin that selectively targets UIIR expressing neurons (cholinergic PPT). In rats the toxin-mediated lesion mimics Progressive Supranuclear Palsy (the most common atypical parkinsonism) on multiple fronts: selective ablation of cholinergic PPT neurons, impaired motor function, and deficits in acoustic startle reaction (MacLaren et al, 2014a; MacLaren et al, 2014b). Our selective cholinergic depletion and a viral-mediated tauopathy rat models are the first to specifically model PSP, and we are further characterizing these models in hope of using them for future drug discovery. 3) During my graduate and post-doctoral training it was found that the central brain administration of neuropeptide S (NPS) in mice enhances memory, is anxiolytic-like (reduced anxiety) and produces hyperlocomotor (increased movement) (Xu et al., 2004; Jungling et al., 2008; Duangdao et al., 2009; Okamura et al., 2011). This is a highly unique behavioral profile. Typically drugs that induce activity and arousal increase anxiety-like behaviors, while drugs that are anxiolytic generally have sedative effects and impair memory. Therefore, the NPS-system could be a therapeutic target for disorders for which fast-acting anxiolytics that augment memory formation would be beneficial (e.g. post-traumatic stress disorder (PTSD)). In collaboration with the Drug Discovery Center at Research Triangle Institute, we are testing new small molecule NPSR-targeted drug-like compounds.
Computational Chemistry; Drug Design; Structural Biology; X-ray Crystallography; Bioinformatics; Protein Folding
The long-term goal of my research has been to understand the role of key active site residues in the mechanism of molecular recognition among various classes of proteins. The primary focus has been study of folate-dependent enzyme pathways, in particular dihydrofolate reductase (DHFR). These enzymes from pathogenic Pneumocystis species are of interest for the design of selective inhibitors for the treatment of AIDS-related pneumonia. Analysis of the structural data from several classes of protein has revealed a great degree of conformational flexibility for ligand binding that result in novel modes of binding to the same active site. Understanding the role of such flexibility has aided in the design of new scaffolds for inhibitor design. Additionally, my lab has the expertise to carry out the necessary molecular biology experiments to clone, express and purify proteins for crystallographic study using both bacterial and insect cell host systems. We have a long-standing, successful collaboration with the Queener lab to study DHFR, particularly from the opportunistic pathogens Pneumocystis jirovecii (pj) and Pneumocystis carinii (pc), found in man and rats, respectively. Our lab is also studying transthyretin (TTR), the thyroid hormone transport protein, characterizing the human protein bound to inhibitors with potential to stabilize the tetrameric structure and ameliorate the effects of filbril formation. Transthyrtetin from lamprey is of interest as it is thought to be the cross-over species in the change of function from a hydrolase to hormone transport function.
Current experiments focus on the dynamics of microtubule assembly in spindles during the process of meiosis using live imaging of fluorescent labeled microtubules. We utilize cranefly spermatocytes isolated into acute cultures containing cells at various stages of cell division that can be studied for several hours. Microtubule dynamics are studied by the technique of fluorescent speckle imaging whereby spermatocytes are injected with low concentrations of fluorescent-labeled tubulin that incorporates into microtubules at low density. This creates a patterned, discontinuous labeling of microtubules that enables quantification of the rates and sites of assembly. We currently are testing the role of tension as a modulator of microtubule polymerization during anaphase. Chromosome kinetochores exert dragging forces on attached microtubule ends favoring microtubule assembly as chromosomes move from spindle equator to spindle poles. However, microtubule disassembly is induced when dragging forces are eliminated by laser ablation of attached chromosomes. These observations may reveal some of the self-organizing mechanisms that control the orderly separation of chromosomes during cell division. In previous experiments, we studied cytoskeletal changes in neuronal growth cones as they navigated through their environment. Reorganization of actin filaments and microtubules was visualized using fluorescent cytoskeletal analogs in neuronal cultures. Dynamic flow of actin filaments in growth cone lamellipodia and their effect on microtubule extension into growth cones was studied to understand the basis of growth cone turning.
Allergy and Immunology; Medical Microbiology; Infectious Disease; Microbiology; Genomics and proteomics; Immunology; Microbial Pathogenesis; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Gene Expression; Signal Transduction; Protein Function and Structure; Bacterial Pathogenesis
Research efforts in my laboratory are focused in the fields of immunology and bacterial pathogenesis, two diverse fields of biomedical research for which I have two separate research groups. Projects in both fields are performed by undergraduates, doctoral and master’s degree students, postdoctoral fellows and senior research associates. One major focus of my laboratory is studying the regulation of mucosal immune responses. We investigate the cellular and molecular events by which Type II heat-labile enterotoxins (HLTs), produced by certain strains of Escherichia coli, modulate immune responses. We have demonstrated that LT-Ilia, LT-IIb and LT-IIc, when co-administered with an antigen, have the capacity to enhance antibody and cellular immune responses to that antigen. Using a variety of immunological and cellular technologies, including flow cytometry, fluorescence resonance energy transfer (FRET) detection, cytokine multiplex analysis, mutagenesis, quantitative Reverse Transcription PCR (qRT-PCR), RNA-sequencing (RNA-Seq) and a variety of transgenic mice, we are investigating the mechanisms by which these immunomodulators productively interact with various immunocompetent cells (T cells, B cells, dendritic cells, macrophages) to induce or suppress cytokine production, costimulatory ligand expression and cellular proliferation. A practical outgrowth of these experiments is the potential to engineer novel recombinant vaccines by genetically fusing antigens from different pathogens to the enterotoxins. Recent experiments have shown that these HLT are lethal for triple-negative breast cancer cells, which has opened a new area of oncological research for the lab. A second focus of my laboratory is to investigate the molecular mechanisms by which adherent-invasive Escherichia coli (AIEC) induce, exacerbate or prolong the symptoms of inflammatory bowel disease (IBD) and Crohn’s disease, two acute and chronic inflammatory diseases of the human gut. In vitro, AIEC strains invade into the cytoplasm of several epithelial cell lines. Using recombinant screening methods and RNA-Seq technologies, we are identifying the genes of AIEC that are required to attach and to invade gut cells.
I am interested in bringing people together who have an interest in anatomy but are trained as educators, artists, computer scientists programmers or graphical designers. For example, a graphical artist by training completed a master’s degree in our department by designing a computer-based tutorial on the anatomy of the renal corpuscle. Other projects include a computer-guided tutorial for the histology laboratory (see http://www.buffalo.edu/news/3016), a highly interactive computer-based examination that has a broad range of applicability, and a computer-based video examination. In the future, I expect to introduce virtual microscopy to our course in histology. I am also interested in the evaluation of computer assisted instruction and the way CAI contributes to learning.
Infectious Disease; Infectious Disease; Microbial Pathogenesis; Vitamins and Trace Nutrient
I care for patients who are hospitalized at Erie County Medical Center where I also serve as the hospital epidemiologist addressing infection control. I teach medical students, residents, and fellows in both hospital and classroom settings. In UB’s schools of medicine and dentistry, I teach a variety of topics including microbiology, pharmacology and toxicology, oral biology, and gastrointestinal systems, host defenses, and global health. I also conduct laboratory research on diarrhea-producing strains of E. coli bacteria. My lab focuses on enteropathogenic Escherichia coli (EPEC), Shiga-toxigenic E. coli (STEC, aka EHEC) and enterotoxigenic E. coli (ETEC). We are working on the role of intestinal host defenses such as nitric oxide and on the immune modulatory effects of adenosine. We have discovered that zinc can directly inhibit the virulence of pathogenic bacteria, and we are working on turning these laboratory findings into treatments. In our work on zinc we collaborate with Michael Duffey, PhD, in the Department of Physiology and Biophysics. Recently we have discovered that zinc can inhibit the development of resistance to antibiotics in Escherichia coli and other bacteria. Zinc does this by its ability to inhibit the SOS response, a bacterial stress response triggered by damage to the bacterial DNA. We are collaborating with Dr. Mark Sutton of Biochemistry to better determine the mechanism of zinc in this regard. I am interested in international medicine and global health and participate in an annual medical mission trip to Honduras, a trip in which student volunteers are encouraged to participate. Closer to home, I am a volunteer physician at Good Neighbors Health Center, a free clinic for the underserved on Jefferson Avenue in Buffalo. Resident physicians are encouraged to volunteer, and students may also be able to arrange clinical experiences. I am Co-Medical Director, with Dr. Ryosuke Osawa, of the Erie County TB Clinic. Learning experiences in my laboratory, in infection prevention and hospital epidemiology, or in international health, may be available for motivated students, residents, and fellows.
Autoimmunity; Bioinformatics; Genomics and proteomics; Immunology; Infectious Disease; Molecular and Cellular Biology; Molecular genetics; Neurobiology
My primary research is in the field of biomedical ontology development. An ontology is a controlled, structured vocabulary intended to represent knowledge within a particular domain. Terms in an ontology have logical relationships to each other and to terms in other ontologies, to allow for reasoning and inference across the ontology. Biomedical ontologies allow annotation and integration of scientific data within particular fields of science and medicine, and their careful curation and logical structure facilitate data analysis. My work in biomedical ontology is strongly informed by my earlier experience in laboratory research in immunology, genetics, molecular biology and virology. My research group works on ontologies for both basic and clinical applications, in collaboration with researchers both at UB and other institutions. I led efforts to revise and extend the Cell Ontology, which is intended to represent in vivo cell types from across biology. We worked extensively to bring it up to community-accepted standards in ontology development, placing particular emphasis on improving the representation of hematopoietic cells and neurons. We are developing the Cell Ontology as a metadata standard for annotation and analysis of experimental data in immunology in support of the National Institute of Allergy and Infectious Diseases (NIAID) ImmPort Immunology Database and Analysis Portal and Human Immunology Project Consortium. We have also developed ways to use the Cell Ontology in support of the analysis of gene expression data linked to cell types and have contributed to the Functional Annotation of the Mammalian Genome (FANTOM) 5 Consortium‘s work on identifying gene transcription start sites across multiple cell types and tissues. My research team is also developing the Neurological Disease Ontology to represent clinical and basic aspects of neurological diseases in order to support translational research in this area. In collaboration with clinical colleagues at UB, we are initially focusing on Alzheimer’s disease and dementia, multiple sclerosis and stroke. We have as well developed a companion ontology, the Neuropsychological Testing Ontology, to aid in the annotation and analysis of neuropsychological testing results used as part of the diagnosis of Alzheimer‘s disease and other neurological diseases. I am a long-term member of the Gene Ontology (GO) Consortium and have a particular interest in the representation of immunology and neuroscience in the GO. I am also involved in UB’s contribution to the Protein Ontology and contribute as well to the work of the Infectious Disease Ontology Consortium, Immunology Ontology Consortium and Vaccine Ontology Consortium. I teach and mentor students at the master’s and doctoral levels, and advise undergraduate, graduate, and medical students in summer research projects as well.
Addictions; Drug abuse; Behavioral pharmacology; Cytoskeleton and cell motility; Gene Expression; Gene therapy; Neurobiology; Neuropharmacology; Signal Transduction; Transcription and Translation
Drug addiction is a disabling psychiatric disease leading to enormous burdens for those afflicted, their friends and family, as well as society as a whole. Indeed, the addict will seek out and use illicit substances even in the face of severe negative financial, family and health consequences. It is believed that drugs of abuse ultimately “hijack” the reward circuitry of the CNS leading to cellular adaptations that facilitate the transition to the “addicted” state As is the case with both rodent models of drug taking, and well as throughout the global human population, not all individuals exposed to drugs of abuse will meet the classical definition of being truly “addicted”. We are looking at how molecular and behavioral plasticity mediates susceptibility to drug abuse and relapse like behaviors.
Biomedical Image Analysis; Biomedical Imaging; Digital Pathology; Image Analysis; Machine Learning; Quantitative Histology; Bioinformatics
Our group specializes in building quantitative image and data analysis algorithms for biomedical datasets. For the past 9 years, I have been developing computerized methods to quantify and analyze large medical imaging datasets. These methods include data processing, object detection / segmentation, feature extraction and selection, dimensionality reduction, and classification (supervised and unsupervised). I strongly believe in translating academic research into real-world products and services. To that end, along with my colleagues, I have worked at a start-up company to bring my work into the marketplace -- an experience that has given me great insight into the business side of academia. This experience broadened my understanding of how basic research is translated into a profitable enterprise, and I believe these lessons have made me a better engineer. I am currently working as an Assistant Professor in the Department of Pathology & Anatomical Sciences at the University at Buffalo, where I am focused on building a teaching and research program for quantitative modeling of anatomy and cell biology. This program will introduce students of both medicine and engineering to pattern classification approaches developed in recent years, applying them to real-world clinical problems.
My research activities involve the study of the three-dimecsional structures of steroids and the enzymes that control their synthesis and metabolism, the binding proteins that influence their tissue distribution and the receptors that control their hormonal action. Of particular interest are short chain dehydrogenase enzymes that control the balance of active and inactive steroids involved in normal processes, neoplasia and hig blood pressure. We are studing the evolution of this family of enzymes that extend form bacteria to man and have as substrates sugars, retinals, steroids and other small molecules. I am also engaged in the study of antibiotics and toxins that form membrane ion channels, the mechanism of ion channel formation, ion channel blocking and ion transplant.
Drug abuse; Behavioral pharmacology; Signal Transduction; Neuropharmacology; Circadian Rhythm/Chronobiology
My lab‘s research seeks to understand the mechanism of action of the hormone melatonin at the MT1 and MT2 G-protein coupled receptors. We study these receptors in the brain and through the body with the goal of identifying ligands that exhibit useful binding affinity and therapeutic potential. Our team of undergraduate and graduate students, postdoctoral fellows, technicians and senior scientists work with each other and with expert co-investigators in medicinal chemistry to discover and develop novel molecules that can mimic or counteract the actions of melatonin. These molecules may help treat a variety of diseases and conditions including insomnia, circadian sleep disorders, depression, seasonal affective disorders, and cardiovascular disease. Our laboratory pursues these investigations from several angles. We assess the localization of the melatonin receptors, examine their cellular and molecular signaling mechanisms,and investigate receptor fate following prolonged exposure to melatonin. We study the distinct roles of selective MT1 and MT2 melatonin receptor ligands in modulating circadian rhythms, methamphetamine‘s ability to induce both sensitization to prolonged exposure, and stimulation of the reward system. We also study cell proliferation, survival, and neurogenesis in the brain, and the changes in gene expression underlying all these processes. Our research ultimately aims to discover novel drugs with differential actions at the MT1 and MT2 receptors. We use molecular-based drug design, computer modeling and medicinal chemistry to design and synthesize small molecules that target these receptors as agonists, inverse agonists and/or antagonists. We then pharmacologically and functionally characterize these molecules using cell-based assays and bioassays and test them in circadian and behavioral animal models.
Gastroenterology; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular and Cellular Biology
Research in my laboratory concerns neurotransmitter and hormone-mediated anion secretion by gastrointestinal secretory tissues like intestinal crypts and liver ducts. I am determining the mechanisms that regulate the basolateral membrane K+ channel, KCNQ1, in anion secretion because these channels play a critical role in secretion by maintaining membrane potential as a driving force for anion exit across the apical cell membrane. Characterization of KCNQ1 K+ channels will help us to understand and remedy defects in anion secretion, especially in diseases like cystic fibrosis. I use electrophysiological techniques, including Ussing chamber, patch-clamp, and Fura-2 fluorescence techniques. I am also studying the mechanisms by which K+ channel antagonists (e.g., Zn2+) block KCNQ1 channels so that anti-secretory, anti-diarrheal drugs can be developed. I have past experience determining the mechanisms by which neurotransmitters regulate K+ channels via inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release transduction pathways. I am also collaborating with Dr. John Crane to define the mechanisms by which Zn2+ inhibits the effects of Enteropathogenic E. coli (EPEC) on epithelial cell death and EPEC-stimulated phosphorylation and activation of the CFTR Cl- channel. There is considerable controversy concerning the role and basis of GI disorders associated with autism. In collaboration with Drs. Randall Rasmusson and Glenna Bett, I am investigating the mechanistic link between autism susceptibility and abnormal GI function. I propose that disorders of cellular Ca2+ homeostasis play a key role in the GI disorders of autism. Using mouse models derived from Cav1.2 Ca2+ channel defect that produces the human disorder, Timothy Syndrome, I am characterizing muscle tension and electrophysiological properties of the Ca2+ channel in intestinal smooth muscle. This information will lead to new approaches to identify therapeutic targets and treatments for autistic spectrum GI disorders and symptoms.
Clinical Neurophysiology; Physical Medicine and Rehabilitation; Neurobiology
As director of UB’s Neuroengineering and Informatics for Rehabilitation Laboratory (NIRlab), I conduct interdisciplinary research in neural engineering, the application of engineering to the neurosciences. My academic and research training in neurotechnology, motor rehabilitation, clinical neurophysiology and cerebrovascular medicine provides me with the expertise for translational research focused on developing computational models and hardware technologies for neural interfaces to monitor and activate beneficial neural function. My research transcends conventional academic boundaries in my overarching goal to treat, cure and even prevent neurological disorders using ‘electroceuticals’--bioelectronics that stimulate the nervous system. Specifically, my research is directed toward an enhanced understanding of the neurophysiological mechanisms associated with the relearning of visomotor function. My special focus on neurorehabilitation uses neuroengineering and informatics to leverage human-machine interfaces. Here, the human brain and body act in concert with biofeedback and multilevel neurostimulation to promote neuroplasticity and lead to neurorestorative therapy. I am developing electroencephalography (EEG) and electromyography (EMG) and near-infrared spectroscopy-based (NIRS) portable multimodal imaging to understand skeletal, muscle and brain physiology during noninvasive electrical stimulation. If achieved, the bench-to-bedside translation of electroceuticals, developed through innovations in computational methods and instrumentation, will have a very high societal impact since neurological disorders—e.g., stroke and dementia-- will likely dramatically increase as the world population ages. I collaborate with researchers from industry and academia locally as well as from across the globe in conducting the interdisciplinary translational research of NIRlab. I welcome undergraduate, graduate engineering students and medical students to work with me. I am particularly interested in medical students who are focused on clinical neurophysiology, physical medicine and rehabilitation, e.g. students from the departments of Neurology, Neurosurgery, Orthopaedics and the Rehabilitation Sciences. Additionally, I teach courses in neural and rehabilitation engineering. My courses are open to engineering students and medical students, especially those with interest in the application of engineering methods to the clinical neurophysiology and rehabilitation sciences.
My research as technical imaging director of the Buffalo Neuroimaging Analysis Center focuses on developing and applying quantitative image analysis methods to neuroimaging data in order to characterize better the onset, progression, and treatment of neurological diseases. In particular, magnetic resonance imaging (MRI) can provide a vast amount of raw data about a variety of brain and spinal cord tissue characteristics, but extracting meaningful clinical and research metrics from these data is still challenging. Modern computer science techniques, however, can play a transformative role in helping physicians assess data they receive from neuroimaging techniques in order to deliver the best possible care to their patients. Highlights of my work include developing and validating a method for detecting and quantifying demyelination and remyelination in vivo, developing a method that dramatically improves the precision of conventional tissue-specific atrophy measurement and creating a technique for characterizing iron deposition in the basal ganglia. This work has had a substantial impact on our understanding of multiple sclerosis (MS) onset and progression, and the first two techniques have been successfully applied in clinical trials to understand better the impact of various therapeutic approaches in MS. My ongoing research in quantitative image analysis is aimed at increasing our understanding of the data available from state-of-the-art neuroimaging. This increased understanding can be directly translated to clinicians to better inform their patient diagnoses and treatment decisions.
Oncology; Cell Cycle; Cell growth, differentiation and development; Gene Expression; Molecular Basis of Disease; Molecular and Cellular Biology; Signal Transduction; Transcription and Translation
Protein phosphorylation is an essential mechanism by which intercellular signals regulate specific intracellular events. Protein kinases, the enzymes catalyzing protein phosphorylation reactions, represent a major superfamily of genes, collectively representing 2% of the protein coding potential of the human genome. Current projects in Dr. Edelman‘s lab are devoted to the role of protein kinases in prostate and ovarian cancer. These projects utilize a wide range of techniques and involve, collaboration with investigators at Roswell Park Cancer Institute to develop protein kinase-targeted therapies for both types of cancer.
Dr. Elkin serves as Professor and Chair of the UB Department of Biomedical Informatics. He is also a Professor of Medicine at the University at Buffalo. Dr. Peter L. Elkin has served as a tenured Professor of Medicine at the Mount Sinai School of Medicine. In this capacity he was the Center Director of Biomedical Informatics, Vice-Chairman of the Department of Internal Medicine and the Vice-President of Mount Sinai hospital for Biomedical and Translational Informatics. Dr. Elkin has published over 120 peer reviewed publications. He received his Bachelors of Science from Union College and his M.D. from New York Medical College. He did his Internal Medicine residency at the Lahey Clinic and his NIH/NLM sponsored fellowship in Medical Informatics at Harvard Medical School and the Massachusetts General Hospital. Dr. Elkin has been working in Biomedical Informatics since 1981 and has been actively researching health data representation since 1987. He is the primary author of the American National Standards Institute’s (ANSI) national standard on Quality Indicators for Controlled Health Vocabularies ASTM E2087, which has also been approved by ISO TC 215 as a Technical Specification (TS17117). He has chaired Health and Human Service’s HITSP Technical Committee on Population Health. Dr. Elkin served as the co-chair of the AHIC Transition Planning Group. Dr. Elkin is a Master of the American College of Physicians and a Fellow of the American College of Medical Informatics. Dr. Elkin chairs the International Medical Informatics Associations Working Group on Human Factors Engineering for Health Informatics. Dr. Elkin is the Editor of the Springer Informatics Textbook, Terminology and Terminological Systems. He was awarded the Mayo Department of Medicine’s Laureate Award for 2005. Dr. Elkin is the index recipient of the Homer R. Warner award for outstanding contribution to the field of Medical Informatics.
Pediatrics; Psychology; Behavioral Medicine
I am a SUNY Distinguished Professor in the Departments of Pediatrics, Community Health and Health Behavior and Social and Preventive Medicine, and the Chief of the Division of Behavioral Medicine. My research interests focus on health behavior change and determinants of eating, physical activity and drug self-administration. I am an internationally recognized authority in the fields of childhood overweight, physical activity, weight control and family intervention. For the past 30 years, I have conducted research relevant to the prevention and treatment of childhood obesity, including mechanisms that regulate intake and energy expenditure in children. I am a fellow in numerous scientific organizations, and have been the President of the division of Health Psychology, APA, and recipient of the American Psychological Association Award for Outstanding Contributions to Health Psychology. I chaired the Behavioral Medicine Study Section, NIH, and served on the Advisory Board for Center for Scientific Research, NIH. I have published over 300 scientific papers and three books.
Protein Function and Structure; Proteins and metalloenzymes; Vitamins and Trace Nutrient
Cytochrome P450 enzymes are powerful catalysts that play integral roles in biochemical pathways throughout nature. In mammals, members of this class of enzyme serve a variety of functions that include drug metabolism, steroid biosynthesis and the activation and deactivation of vitamin D, to name a few. Cytochrome P450 enzymes are also heavily involved in bacterial and plant biochemistry. The overall goal of our research is to use a combination of biochemical and biophysical tools to investigate structure and function in class I cytochrome P450 enzymes, thereby contributing toward an understanding of how this important class of enzymes work as well as informing the design of therapeutics. This goal is divided between two efforts. First, we are interested in characterizing the substrate and redox partner interactions of the enzyme CYP24A1, the P450 responsible for deactivating vitamin D. Describing the interaction between CYP24A1 and vitamin D has the potential to illuminate how the vitamin D structure becomes modified at a particular site. This insight could impact the design of vitamin D analogs with benefits for an array of human health conditions, including bone density disorders, diabetes and chronic kidney disease (CKD). A parallel effort in our group is a structural study of the enzyme CYP121 of Mycobacterium tuberculosis, the disease-causing pathogen in tuberculosis (TB). The resurgence of standard TB and the rise of drug-resistant forms of TB are quickly becoming a global pandemic, with TB claiming more lives worldwide in 2014 than HIV. CYP121 is essential for survival of the bacterium and thus has emerged as one of the more promising antitubercular drug targets. Students and postdocs joining my lab will be exposed to a multidisciplinary set of research tools, including expression and purification of recombinant membrane protein, nuclear magnetic resonance, protein X-ray crystallography and P450 ligand binding assays.
Neurology; Cytoskeleton and cell motility; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Signal Transduction; Inherited Metabolic Disorders; Transgenic organisms
My laboratory seeks to understand the molecular basis of myelination and myelin diseases. Myelin is a multi-lamellar sheath that invests large axons and permits rapid conduction of nerve signals. Failure in myelin synthesis and myelin breakdown cause several important neurological diseases, including multiple sclerosis, leukodystrophies and peripheral dysmyelinating neuropathies. In some of these diseases, genetic mutations cause defects in cytoskeletal, adhesion and signaling molecules. I work with a team of undergraduate and graduate students, postdoctoral fellows, technicians, senior scientists and many international collaborators to discover how these molecules normally coordinate cell-cell and cell-extracellular matrix interactions to generate the cytoarchitecture of myelinated axons. We use a variety of approaches, including generation of mice carrying genetic abnormalities, cultures of myelinating glia and neurons, imaging, biochemistry and morphology to understand the role of these molecules in normal and pathological development. By comparing normal myelination to the abnormalities occurring in human diseases, we aim to identify molecular mechanisms that pharmacological intervention might correct. For example, we described how the protein dystroglycan associates with different proteins, some of which impact human neuropathies, depending on a proteolitic cleavage that can be regulated to improve the disease. Similarly, we found that molecules such as integrins and RhoGTPAses are required for glia to extend large processes that will become myelin around axons. In certain neuromuscular disorders, defective signaling pathways that converge on these molecules cause failure to produce or mantain an healthy myelin Finally, in collaborations with scientists and clinicians in the Hunter J. Kelly Research Institute, we are generating transgenic forms of GalC, an enzyme deficient in Krabbe leukodystrophy, to investigate which cells requires the enzyme. Investigating how GalC is handled may help find a cure for this devastating disease.
Neurology; Neurodegenerative disorders; Pathophysiology; Apoptosis and cell death; Cytoskeleton and cell motility; Molecular and Cellular Biology; Molecular genetics; Neurobiology; Protein Folding; Gene Expression; Transcription and Translation; Signal Transduction; Toxicology and Xenobiotics
My research is aimed at finding the cause and a cure for Parkinson’s disease. Parkinson’s disease (PD) is defined by a characteristic set of locomotor symptoms (rest tremor, rigidity, bradykinesia and postural instability) that are believed to be caused by the selective loss of dopaminergic (DA) neurons in substantia nigra. The persistent difficulties in using animals to model this human disease suggest that human nigral dopaminergic neurons have certain vulnerabilities that are unique to our species. One of our unique features is the large size of the human brain (1350 grams on average) relative to the body. A single nigral dopaminergic neuron in a rat brain (2 grams) has a massive axon arbor with a total length of 45 centimeters. Assuming that all mammalian species share a similar brain wiring plan, we can estimate (using the cube root of brain weight) that a single human nigral dopaminergic neuron may have an axon with gigantic arborization that totals 4 meters. Another unique feature of our species is our strictly bipedal movement, which is affected by Parkinson’s disease, in contrast to the quadrupedal movement of almost all other mammalian species. The much more unstable bipedal movement may require more dopamine, which supports the neural computation necessary for movement. The landmark discovery of human induced pluripotent stem cells (iPSC) made it possible to generate patient-specific human midbrain dopaminergic neurons to study Parkinson’s disease. A key problem for dopaminergic neurons is the duality of dopamine as a signal required for neural computation and a toxin as its oxidation produces free radicals. Our study using iPSC-derived midbrain dopaminergic neurons from PD patients with parkin mutations and normal subjects shows that parkin sustains this necessary duality by maintaining the precision of the signal while suppressing the toxicity. Mutations of parkin cause increased spontaneous release of dopamine and reduced dopamine uptake, thereby disrupting the precision of dopaminergic transmission. On the other hand, transcription of monoamine oxidase is greatly increased when parkin is mutated. This markedly increases dopamine oxidation and oxidative stress. These phenomena have not been seen in parkin knockout mice, suggesting the usefulness of parkin-deficient iPSC-derived midbrain DA neurons as a cellular model for Parkinson’s disease. Currently, we are using iPS cells and induced DA neurons to expand our studies on parkin to idiopathic Parkinson’s disease. We are also utilizing the molecular targets identified in our studies to find small-molecule compounds that can mimic the beneficial functions of parkin. The availability of human midbrain DA neurons should significantly speed up the discovery of a cure for Parkinson’s disease.
Apoptosis and cell death; Inherited Metabolic Disorders; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Regulation of metabolism; Transgenic organisms; Vision science
Our lab is focused on studies of retinal degenerations caused by metabolic defects, particularly dyslipidemias involving defective cholesterol metabolism (e.g., Smith-Lemli-Opitz syndrome), using pharmacological and transgenic animal models. Current studies are focused on the role of lipid and protein oxidation in the underlying mechanisms of photoreceptor cell death in such retinal degenerations, using a combination of genomic, proteomic, and lipidomic approaches.
Bioinformatics; Genomics and proteomics; Immunology; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Gene Expression
The current focus of my lab is on iron metabolism in animals and humans. From the practical viewpoint, iron is an important nutrient, but its ability to act in the ferrous and ferric state also makes it toxic. Thus, iron deficiency is the most frequent disorder in the world and hereditary hemochromatosis (HH) is the most common Mendelian disorder in the United States. Our research is related to erythroid differentiation on the fundamental level and to genetic and acquired diseases on the applied level, with four long-term themes: 1.) analysis of the molecular basis of differential gene expression among tissues and during development, with hemoglobin synthesis and red blood cell (RBC) development as models; 2.) application of molecular and genetic advances to inherited diseases; 3.) iron metabolism; 4.) study of gene variation in populations and divergence of gene loci during evolution. New vistas have opened recently for the anemia of chronic diseases, leading us to re-exam how microbes and their human hosts fight for iron. We approach these issues by working on rodent models like the Belgrade rat, plus a series of genetically engineered mice. The rat has a hypochromic, microcytic anemia inherited as an autosomal recessive. The defect is in an iron transporter called DMT1 (or slc11a2, previously called Nramp2 or DCT1) that is responsible for iron uptake by enterocytes and is also responsible for iron exiting endosomes in the transferrin cycle. The rats appear to have a severe iron deficiency, and although dietary iron and iron injection increase the number of RBCs, they do not restore the RBCs nor the rat itself to a normal phenotype. Recent discoveries show that DMT1 is ubiquitous and responsible for transport of other metals such as Mn and Ni. It occurs in the kidney, brain and lung at even higher levels than in the GI tract or in erythroid cells. It also has multiple isoforms, and we have cloned them and developed cell lines that express high levels of particular isoforms. We have specific antibodies to the isoforms and assays for each of the mRNAs too. Future projects in my lab will continue to address whether DMT1 is dysregulated in HH. We will also tackle how DMT1 functions in neurons, pneumocytes and other tissues, look at isoforms of DMT1 under circumstances where we suspect that they must have different functions from one another, and examine DMT1’s relevance to iron metabolism and human disease. Because we cloned the gene and identified the mutation, a number of molecular and cellular approaches can now be used. As evidence indicates that metal ion homeostasis fails in Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, research on DMT1 has opened new vistas for these disorders.
Bioinformatics; Cell growth, differentiation and development; Genomics and proteomics; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Gene Expression; Stem Cells; Transgenic organisms
My research goal is to gain a better understanding of how proteins that interact with DNA regulate RNA transcription, DNA replication and metazoan development. I mentor undergraduate and graduate students in my lab; we focus on the structure and function of the Nuclear Factor I (NFI) family of site-specific DNA binding proteins, and we are investigating their roles in development. Our work has been made possible by our development of loss-of-function mutations of the NFI genes in the mouse and C. elegans. We are addressing four major questions in my laboratory and in collaboration with a number of talented collaborators: What is the structure of the NFI DNA-binding domain? How does NFI recognize and interact with DNA? Does NFI change the structure of DNA when it binds? What proteins interact with NFI to stimulate RNA transcription and/or DNA replication? These research questions are explored in my lab through two major projects focused on the role of NFIB in lung development and the role of NFIX in brain development. When NFIB is deleted from the germline of mice the animals die at birth because their lungs fail to mature normally. This provides a good model for the problems that occur with premature infants, whose lungs also fail to mature normally. We are using this model to determine how NFIB promotes lung maturation with the goal of being able to stimulate this process in premature infants. In our NFIX knockout animals, the brains of the animals are actually larger than normal and contain large numbers of cells in an area known to be the site of postnatal neurogenesis. We have evidence that NFIX may regulate the proliferation and differentiation of neural stem cells, which produce new neurons throughout adult life. Our aim is to understand the specific target genes that NFIX regulates in the adult brain to control this process of neurogenesis.
Structural Biology; X-ray Crystallography; Microbial Pathogenesis; Microbiology; Protein Function and Structure; Proteins and metalloenzymes
My research program aims to understand how bacteria produce natural products, small molecules that are secreted from the cell to adapt to diverse environments. These molecules allow the bacteria to compete with other microbes or, in the host-pathogen setting, to establish or exacerbate an infection. Natural product biosynthesis may therefore serve as a target for antimicrobial development. My lab uses a variety of techniques to examine these pathways. A core approach is to use X-ray crystallography to determine the molecular structure of proteins that catalyze important steps in natural product biosynthesis. Structural observations are tested and validated using biochemical techniques to examine the catalytic reactions. Finally, molecular and cellular techniques are used to examine biosynthetic gene cluster activity in the cell. These studies will inform efforts to engineer enzymes to produce novel natural product and identify new products of previously uncharacterized pathways. I have a long-standing interest in the Nonribosomal Peptide Synthetases (NRPSs), a family of large, multidomain enzymes that produce important peptide natural products like the antibiotic vancomycin or the anticancer agent bleomycin. NRPSs operate like an assembly line in which the nascent peptide is attached to a carrier domain that shuttles the synthetic intermediates to neighboring catalytic domains. The carrier and catalytic domains are often joined in a single polypeptide that is thousands of residues in length. By examine the crystal structures of large NRPS proteins, we have determined some of the features that enable this fascinating biosynthetic mechanism. Many NRPS products are siderophores, small molecules that bind iron and are required for growth in the pathogenic environment. My lab also studies aerobactin, an NRPS-independent siderophore pathway that is a virulence factor for hypervirulent Klebsiella pneumoniae. We have biochemically and structurally characterized the aerobactin biosynthetic pathway and have developed an approach to find inhibitors of aerobactin biosynthesis that may be tools to probe the pathway chemically to inhibit growth of this human pathogen.
Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Neurobiology; Neuropharmacology; Signal Transduction
Synaptic transmission is a fundamental mechanism that mediates communication between neurons in the brain. My Laboratory is interested in delineating the mechanisms and regulation of synaptic transmission in the central nervous system. In particular, we investigate the mechanisms by which G-protein coupled receptors, including endocannabinoid receptors, gate synaptic transmission and plasticity. We are also interested in the mechanisms of synaptic homeostasis induced by prenatal and postnatal exposure to stress and drugs of abuse. We use a electrophysiological, genetic, optogenetic and behavioral approaches the delineate the synaptic mechanisms underlying addiction and other mental disorders.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Genomics and proteomics; Molecular genetics; Signal Transduction
Research in my laboratory investigates the genetic regulatory circuitry that controls how cell fates are determined during development. We focus on two key aspects, intercellular signaling and transcriptional regulation, using primarily the fruit fly Drosophila melanogaster due to its extremely well-annotated genome and amenability to experimental manipulation. All conclusions, however, are expected to relate directly to mammalian (including human) gene regulation. Recently, we have also started investigating the regulatory genomics of other insect species of both medical and agricultural importance, beginning with the development of methods for regulatory element discovery in species with fully sequenced genomes but little functional, experimental data. A defining feature of my laboratory is that it takes both wet-lab and computational/bioinformatics approaches to studying the same set of problems about development and transcriptional regulation; hypotheses and ideas generated using one set of methods are tested and explored using the other. Current research in the laboratory falls into two main areas: 1) discovery and characterization of transcriptional cis-regulatory modules (CRMs), and 2) mechanisms of specificity for receptor tyrosine kinase (RTK) signaling. The combined results of these studies will provide insight into gene regulation, genome structure, intercellular signaling, and the regulatory networks that govern embryonic development. My group is also heavily involved in biocuration through our development and maintenance of REDfly, an internationally-recognized curated database of known Drosophila transcriptional cis-regulatory modules (CRMs) and transcription factor binding sites (TFBSs). Despite more than 25 years of experimental determination of these elements, the data have never been collected into a single searchable database. REDfly seeks to include all experimentally verified fly regulatory elements along with their DNA sequence, their associated genes, and the expression patterns they direct. REDfly is by far the most comprehensive database of regulatory elements for the higher eukaryotes and serves as an important resource for the fly and bioinformatics communities.
Molecular and Cellular Biology; Neurodegenerative disorders; Transcription and Translation; Signal Transduction; Toxicology and Xenobiotics
My lab studies the receptor signaling mechanisms for a family of neurotrophic factors that includes ciliary neurotrophic factor (CNTF), leptin, interferon gamma, and cardiotrophin-1. These factors use the Jak/STAT pathway to regulate neuronal survival, development and response to trauma. Our interests are in how activity of the receptors and their pathway components are regulated. Currently this has focused on the impact of cellular oxidative stress on the inhibition of Jak tyrosine kinase activity. Increases in oxidative stress in neurons result in the blockade of not only CNTF family factor effects, but of many other cytokines that also use the Jak/STAT pathway for signaling such as interferons and interleukins. Non-nerve cells appear resistant to these effects of oxidative stress. Ongoing projects include testing the theory that environmental contaminants known to increase oxidative stress in cells may promote neurodegenerative diseases by inhibiting growth factor signaling. We have been studying the effects of certain heavy metals (cadmium & mercury) and pesticides (e.g. rotenone) on nerve cells in culture to determine the molecular basis for Jak inhibition. Another examines a possible role of oxidative stress in obesity. This study tests the hypothesis that the loss of the ability of the hormone leptin to regulate metabolism and appetite during obesity is a result of oxidative reactions that inhibit Jak-mediated signaling in the hypothalamus and other brain regions.
Ear, Nose, Throat (Otolaryngology); Oncology; Plastic Surgery for Head (Ear, Nose,Throat); Cell growth, differentiation and development
Wesley L. Hicks Jr., M.D., is chair of the Head and Neck/Plastic & Reconstructive Surgery Program at Roswell Park Cancer Institute in Buffalo, NY. Dr. Hicks is Board Certified by the National Board of Medical Examiners and the American Board of Otolaryngology. He is also a tenured Professor of Otolaryngology/Head and Neck Surgery and Professor of Neurosurgery and Bioengineering at the University at Buffalo School of Medicine and Biomedical Sciences. His research interests focus on tissue engineering, wound healing and mechanisms involved in wound repair. His laboratory is studying novel work in bioengineered devices for enhanced wound repair, as well as cellular microenvironment effecting tissue remodeling and repair. Dr. Hicks was recently named one of the nation’s Top Cancer Doctors by Newsweek magazine and is a recipient of the American Academy of Otolaryngology’s Head and Neck Surgery Honor Award. He was also selected as one of the top 100 physicians in the nation by Black Enterprise magazine. He earned his dental degree at Meharry Medical College and his medical degree at the University at Buffalo School of Medicine and Biomedical Sciences. He completed his residency in Otolaryngology, Head & Neck Surgery at the Manhattan Eye, Ear and Throat Hospital, New York Hospital — Cornell Medical Center, Memorial Sloan-Kettering Cancer Center, New York, NY, and his Fellowship in Head & Neck Surgery at Stanford University Medical Center, Palo Alto, CA. Dr. Hicks is a member of a number of professional organizations, including the National Medical Association, the Triologic Society, the American Medical Association, the American Academy of Otolaryngology/Head & Neck Surgery, the American College of Surgeons, the American Head & Neck Society, and the Society of Black Academic Surgeons. He was a Senior Examiner for the American Board of Otolaryngology. His community affiliations include board memberships on the Board of Directors of HealthNow Inc./BlueCross BlueShield of New York State, the Urban League, the advisory board of First Niagara Bank and WBFO — the National Public Radio (NPR) affiliate. He also is a Commissioner of the Niagara Frontier Transportation Authority. Dr. Hicks has authored or co-authored more than 200 journal publications, book chapters and abstracts, and has been issued a number of patents related to his interest in tissue engineering and wound healing.
Pathophysiology; Cytoskeleton and cell motility; Endocrinology; Eukaryotic Pathogenesis; Gene Expression; Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; Regulation of metabolism; Transcription and Translation
In my laboratory, we are interested in structural components of the cell, their role in establishing and regulating cellular functions, and how this regulation translates into physiological consequences in health and disease. We have two major focus areas: 1) The role of cytoskeletal elements in prostate cancer development and progression and 2) The role of nucleoskeletal elements in establishing and maintaining nuclear structure and function. 1) The majority of death from cancer is caused by metastasis, the spreading of cancer cells from the site of a primary tumor to other body parts. We use a combination of biochemical, cell biological, physiological, and translational approaches to elucidate the mechanisms that are involved in the acquisition of metastatic phenotypes. Specifically, we focus on the role that myosins play in this process. We are also interested in how dietary fats can contribute to the development of metastatic phenotypes in prostate cancer cells. 2) Aberrations in nuclear structure and dynamics are the underlying cause of diseases ranging from cancer to premature aging. We are interested in the role of nuclear actin and myosins in regulating dynamic nuclear processes such as nucleolar assembly and functions in health and disease.
Neuroimmunology; Behavioral pharmacology; Gene therapy; Immunology; Molecular and Cellular Biology; Molecular Basis of Disease; Neurobiology; Gene Expression; Signal Transduction; Protein Function and Structure; Neuropharmacology
My research spans three interrelated fields: chronic pain, depression and inflammation. Experiments in my laboratory focus on how brain-derived pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF), function as modulators of brain-body interactions during neuropathic pain and how brain-TNF is involved in the mechanism of action of antidepressant drugs. My overall goal is to advance knowledge of, and therapeutic efficacy for pain, depression, neuro-inflammation and drug addiction. This research is based on my earlier work showing that neurons produce the pro-inflammatory cytokine TNF and that the production of TNF by macrophages is regulated by neurotransmitters. Cytokines and neurotransmitters are principal signaling molecules that mediate bidirectional communication between the nervous and immune systems--the crosstalk important in maintaining homeostasis. Consequently, aberrant production of either of these two classes of mediators could profoundly affect signaling by the other, thereby impacting health. A shift in balanced cytokine-neuron interactions that regulate neurotransmitter release in the central nervous system (CNS), and that have potential behavioral consequences, manifest themselves as states of depression and chronic pain. My research uses both cell systems and animal models to test these hypotheses. Colleagues and I use a combination of imaging techniques to localize cytokine production, bioassays and ELISA (enzyme-linked immunosorbent assays) for pharmacological and functional analyses, electrophysiological (brain slice stimulation) and molecular methods for our studies. In addition to investigating neuron functioning in the brain, trainees in my laboratory also study the peripheral macrophage, a major source of TNF during inflammation. Specifically studying neurotransmitter regulation of TNF production in the periphery is enhancing our knowledge of how the brain controls a peripheral inflammatory lesion. Our studies are designed to investigate the mechanisms of centrally mediated pain as associated with immune dysfunction and to elucidate mechanisms of drugs used to treat such pain states. My projects are evolving to investigate the mechanisms and neural pathways involved in TNF neuromodulator functions during chronic pain (due to peripheral nerve injury and diabetes) and stress-induced depressive behavior. We also study mechanisms contributing to the comorbidity of chronic pain and depression. I collaborate with researchers in several UB departments and at other institutions. Our projects include using noninvasive methods for delivery of anti-TNF therapeutics for chronic pain, elucidating the neural-immune mechanisms involved in the rapid recovery afforded by centrally administered anti-TNF therapy and using nanotechnology-mediated, targeted gene silencing within the CNS. I am invested in helping my undergraduate and graduate students, medical residents and postdoctoral fellows realize their potential and achieve their goals. Previous students have advanced professionally and hold clinical, academic and industrial positions.
Cardiovascular Disease; Diagnostic Radiology; Neuroradiology - Radiology; Radiological Physics; Vascular and Interventional Radiology; Vision science
I am an Assistant Professor with a dual appointment in the Biomedical Engineering Department and Neurosurgery. I am the director of the Endovascular Devices and Imaging lab at Canon (former Toshiba) Stroke and Vascular Research Center. My research career focuses on improvement of endovascular image guided interventions and encompasses three major components: medical imaging, computer programming and endovascular device development. The greatest breakthrough of my team in the last three years is the development of complex 3D printed (3DP) vascular patient specific phantoms based on 3D imaging. Using my previous experience in developing CT reconstruction algorithms and 3D data analysis, this step came naturally. We are using these phantoms to test devices and validate software such as CT-FRR, parametric imaging and material decomposition using spectral CT. The 3DP phantoms we develop are probably some of the most complex reported in literature. We created new tools for 3D mesh manipulation and workflow to build complex vascular trees, which maintain vessel down to 400 microns diameter. My team collaborates directly with 3D printing industry and engineers in academy, to optimize the 3DP materials and match tissue mechanical properties. As center of excellence for 3D printing, we contribute to identification of new clinical applications for the 3DP technology, 3DP material development, and testing, and software development. One of the challenges my team is tackling, is the 3D printing material and 3D design optimization to build structures with controlled mechanical properties. In the last two years, my research focused on how to use the 3D printing technology to create digital structures which can simulate mechanical properties of vascular tissue, vascular networks and arterial disease. My effort is directed toward developing methods to warp 3D structures and embed them within the arterial wall. The embedded structures could be printed with different materials to different mechanical properties. This approach will allow optimization of phantom physical properties which match those of the arteries. Thus, by combining the 3D design with the new polymers used for the 3D printing while maintaining the patient specific geometry, I plan to develop a vascular model which will behave and react identical as a human vessel, both healthy and diseased. On a secondary effort on 3DP, my team is involved in developing implantable devices; we are collaborating with metal printing industries in testing methods to develop 3DP patient specific devices. We are able to reproduce coronary stents, which match the physical size/geometry of those used in current practice. However, mechanical and corrosion aspects need more investigations. In this context, I believe that additive manufacturing can be another path towards personalized medicine, by allowing manufacturing of patient specific devices rather than one size fits all kind of approach used by current device manufacturers. Concerning my involvement in the scientific community, in the last two years, I became deeply involved with the effort to implement the new advances of 3D printing into a clinical setting. I have given presentations and symposiums at conferences such as RSNA where I emphasized the new additive manufacturing advances and the close relation with the 3D medical imaging. The new digital material technologies, the improved resolution and fast building time make this technology practical for the high pace workflow in the hospitals. As of now I am involved with Special Interest Group from RSNA for standardization of 3DP printing operations in hospitals and development of a DICOM standard associated with the workflow and manufacturing of 3D printed medical objects.
The human immunodeficiency virus (HIV) is now considered a chronic disease in the developed world. In underdeveloped areas where access to antiretroviral therapy is limited, however, it remains a devastating disease contributing to grave socioeconomic problems. The goal of my research is to expand our knowledge of pathogen interactions with cellular membranes by developing a detailed understanding of the mechanism of HIV entry and by studying co-infection of HIV with the pathogenic fungus Cryptococcus neoformans in human macrophages. The first step of HIV infection is HIV entry when the envelope protein complex on the surface of the virus comes into contact with the cellular receptors, glycoprotein CD4 and coreceptor, and mediates merging of the viral and cellular membranes leading to delivery of the viral genetic material. Mechanistic studies help to inform the development of inhibitors to HIV entry that will be beneficial on both therapeutic and prophylactic levels. The envelope protein complex is the machinery that gets the virus into the cell; as such, it is also a prime target for the development of vaccines. HIV/AIDS often kills by priming the host for opportunistic infections. Cryptococcal meningitis is one of the leading killers of AIDS patients. The human macrophage is the cell type tasked with ingesting and clearing microbes. In my lab, we are working to define the role of the human macrophage in the copathogenesis of the opportunistic fungus Cryptococcus neoformans and HIV during AIDS progression. The mechanisms of host-microbe interactions also serve as templates for the design of novel drug regimens, including immunotherapy. We have recently utilized our extensive experience in the study of how HIV enters the cell to begin studies in Ebolavirus entry which has a similar mechanism. We are developing inhibitors to the process of Ebolavirus entry and using developments in inhibition to study the mechanism of attachment and membrane fusion into multiple cell types. It is my objective throughout my career to provide vital basic research in virology and cell biology in order to advance medical treatment and prevention. As an academic researcher, I put a strong emphasis on the training and mentoring of young scientists in my lab, and I participate in the T35 training grant from the National Institutes of Health that UB and Roswell Park Cancer Institute jointly secured. I train master’s and PhD students as well as postdoctoral fellows in the departments of Microbiology and Immunology and Biochemistry. I also mentor undergraduates in research projects; these students may come to me independently or through UB’s Center for Undergraduate Research and Creative Activities (CURCA) in which I am active. I direct undergraduate studies for my department, and I am the course director for Biomedical Microbiology, my department’s large undergraduate basic science course.
Pediatric Rheumatology; Pediatrics
I have a broad interest in rheumatic diseases in children. I am particularly interested in juvenile idiopathic arthritis (JIA) and improving the time frame over which we can achieve remission in this family of illnesses. With newer medications, we are making significant progress, but we still have much to learn. I also have a keen interest in children with systemic lupus and inflammatory muscle disease. Over time, because of my own Native American ancestry (Mohawk), I have particularly enjoyed the opportunity to work with indigenous American children, whose expression of rheumatic disease and treatment response are slightly different from the broader population. We hope that tribal health systems will see our pediatric rheumatology service as the “go-to” place for children with arthritis and related illnesses. I spend most of my time doing research, and my laboratory focuses on mechanisms through which genes and so called “DNA dark matter” are turned off and on through the course of successful therapy in JIA. We study these processes using state-of-the-art ChIP-sequencing, DNA methylation sequencing, and RNA sequencing techniques. These projects consist of collaborating with colleagues at the New York State Center of Excellence in Bioinformatics (COE). I also spend considerable time working with indigenous American communities on a broad range of child health issues. I currently chair the American Academy of Pediatrics Committee on Native American Child Health, which has a strong interest in why rheumatic diseases are so common and severe in indigenous American children. We are particularly focused on so-called epigenetic factors, stemming from historical traumas and cultural dislocation that may play a role in how rheumatic diseases are expressed in indigenous children. One of the most rewarding parts of my career has been the opportunity to mentor talented Native American students and assist them in developing their interests in science and medicine. Previous students include a veritable “Who’s Who” among young Native American physicians, and I am working to establish and foster partnerships for UB with local colleges and tribes to develop a rich resource of Native American physician scientists in New York State.
My research program has been focused on innate immune signaling and cytokine biology as it relates to inflammation, bone loss, and oral cancer progression. My translational research explores the roles of posttranscriptional cytokine regulation in oral inflammation with the ultimate possibilities of developing novel therapies to control chronic oral inflammation.
Cardiovascular Disease; Cytoskeleton and cell motility; Molecular Basis of Disease; Molecular and Cellular Biology
My primary research interest is the behavior of endothelial cells, which form the inner lining of blood vessels and are key players in the remodeling events that occur during wound healing, aneurysm formation, tumor growth, and a wide variety of disease conditions. There are two questions about endothelial behavior that drive most of the research in my laboratory: (1) How does an endothelial cell migrate during wound healing and blood-vessel remodeling? We are particularly interested in the motor protein, myosin II, and how it exerts force within the cytoskeleton to push or pull the cell as it moves. In order to study the organization and movements of cytoskeletal proteins - and not just there biochemical properties - we use a variety of light microscopic methods to examine the dynamics and biochemistry of cytoskeletal proteins in living migrating endothelial cells. We also use conventional biochemical, genetic, and pharmacological manipulations to investigate the regulatory events that control myosin II behavior in situ. (2) How do endothelial cells sense and respond to their mechanical environment? Blood vessels remodel to accommodate long-term changes in blood flow. Certain flow environments can cause destructive remodeling that leads to cerebral aneurysms (local “ballooning” of vessels). Working with biomedical engineers in the laboratory of Dr. Hui Meng at the Toshiba Stroke Research Center, we use cell culture and whole animal systems to examine how endothelial cells respond to specific hemodynamic micro-environments in order to understand the mechanism and regulation of flow-induced remodeling, especially as it relates to cerebral aneurysms. A third interest is understanding the response of cultured endothelial cells to electrical fields, which have been shown to orient endothelial migration in vitro and to suppress edema in vivo by enhancing the endothelial permeability barrier.
Membrane Transport (Ion Transport); Neurobiology; Protein Function and Structure; Proteins and metalloenzymes; Vitamins and Trace Nutrient
The long term goal of the research conducted in my lab is to learn about the general principles that organisms use to acquire and metabolize the essential nutrients iron, manganese and copper. Since in eukaryotes, iron metabolism, for example, depends on the activity of copper-containing enzymes called ferroxidases, we examine the trafficking copper in cells as well. In addition, as divalent metal ions, manganese and ferrous iron share many of the same trafficking pathways. The first challenge for a cell is to scavenge these metals from the environment. This is true for a yeast cell in culture, for an epithelial cell in your intestine, an endothelial cell in the capillaries in the brain, or a neuron. The second challenge is to efficiently and correctly partition these metals in the cell for subsequent utilization and storage. Ultimately the cell or organism will have to regulate the accumulation of these metals and to ensure that they are not allowed to roam "free" since all three are toxic. Yet all are essential micronutrients, as well. They are required in fundamental cellular processes such as cellular respiration in all organisms, and for vital physiologic functions such as oxygen transport in blood and muscle. The brain has a strong requirement for iron and copper to support the elevated energy metabolism needed to support neuronal function; manganese is essential to neurotransmitter synthesis. This essentiality is contrasted by cytotoxicity that results from their strong tendency to generate oxygen radicals which in turn destroy key cellular components. For example, iron uptake into the brain must be tightly regulated, a process we focus in our research. Failure of this regulation can result in a variety of brain pathologies particularly those that result in degeneration of neuronal function. We study in detail the role of the amyloid precursor protein and alpha-synuclein in iron and manganese trafficking and how these functions are related these proteins‘ roles in neurodegenerative disease.
Cardiology; Cardiovascular Disease; Cell growth, differentiation and development; Gene Expression; Molecular and Cellular Biology; Signal Transduction; Stem Cells
As a general cardiologist, I diagnose and treat a wide range of problems that affect the heart and blood vessels, including but not limited to coronary artery disease, valvular heart disease, heart failure, diseases of the myocardium and pericardium, cardiac arrhythmias, conduction disorders and syncope. I attend on the inpatient Coronary Care ICU (CCU), Cardiac Step-down Unit, and Cardiology Consult service at Buffalo General Medical Center as well as see patients in my outpatient clinic. In addition to treating pre-existing cardiac conditions, I also believe in strong preventive care and addressing modifiable risk factors for coronary disease. I take time to get to know my patients, and I talk with them about measures they can take to reduce their risk for cardiovascular disease and improve their health. As a clinician-scientist, I have a special interest in developing new stem cell based treatments for heart disease. My research is focused on understanding what stem cell secreted factors are responsible for improved heart function, what their targets are and how these can be modulated to develop new cell-free therapies that can help patients with a wide spectrum of coronary disease and heart failure. I welcome medical students, graduate students, residents and fellows to conduct research with me in my lab. As a native Buffalonian, I am honored to partner with the patients in our community to help improve their heart health and cardiac knowledge base. I am equally excited to be involved in shaping the next generation of physicians through the teaching I conduct at the medical student, resident and fellow level.
Concussion; Sports Medicine; Sports Medicine - Internal Medicine
As a primary care sports medicine physician, my goal is to provide the best evidence-based evaluation and treatment practices to patients with concussion and post-concussion syndrome and to conduct clinical and physiological research on these conditions. I currently serve as medical director of the University at Buffalo Concussion Management Clinic, which is located at UB South Campus. This is the first center in the United States to use a standardized treadmill test to establish recovery from concussion and to use exercise in the rehabilitation of patients with prolonged concussion symptoms. I’m also the director of outcomes research for the Department of Orthopaedics and program director for the UB Primary Care Sports Medicine fellowship. My primary research interest is the investigation of the basic mechanisms of the disturbance of whole body physiology in concussion and how to help to restore the physiology to normal to help patients recover to safely return to activity and sport. I have published in the fields of orthopedics, sports medicine, physiology, nutrition, concussion and post-concussion syndrome. As a professor of Clinical Orthopaedics, Internal Medicine, and Rehabilitation Sciences at the University at Buffalo School of Medicine and Biomedical Sciences, I enjoy educating the next generation of physicians. I am proud to say that the educational experience at UB exposes young physicians to exceptional patient care based upon the latest research and that their experience is informed and enhanced by immersion in the research experience itself.
Research in my laboratory is focused on stem cell biology, engineering, and therapeutic applications with an emphasis on cardiovascular repair. We have explored the immunomodulatory property of bone marrow mesenchymal stem cells (MSCs) in our cell transplantation studies, and found that large quantities of human and porcine MSCs can be implanted in immunocompetent pigs, mice, and hamsters without inducing inflammatory immune responses in the host. Our research shows that MSCs improve cardiac function in the porcine myocardial ischemia and hamster heart failure models. Implanted MSCs promote tissue regeneration by recruiting bone marrow progenitor cells and activating local host stem cell niches. These processes are mediated by inter-tissue cross-talk mechanisms involving signaling molecules such as JAK/STAT3, integrins, VEGF receptors, and Wnt/b-catenin. Our long-term goal is to generate clinically relevant stem cell information that may be used to achieve robust therapeutic effects for a broad spectrum of human diseases and lower the cost of future stem cell therapy.
Infectious Disease; Bioinformatics; Microbial Pathogenesis
My clinical interest work focuses on infectious diseases, particularly those caused by Staphylococcus aureus. I practice medicine at the VA Western New York Healthcare System, where I am Chief of the Infectious Disease Section. The service here treats veterans with a wide variety of infectious diseases, including HIV and hepatitis C. I follow both inpatients and outpatients on this clinical service. Medical students, residents, and fellows evaluate and follow infectious disease consultations with me on the inpatient service. I teach extensively in the Medical School, and serve as Vice Chair for Education in the Department of Medicine. I enjoy working with students throughout the full spectrum of medical education, from first-year medical students to senior fellows in Infectious Disease. My research interests dovetail with my clinical work. I study Staphylococcal infections, particularly complications related to S. aureus bloodstream infections. My laboratory uses advanced molecular biology techniques to identify bacterial virulence factors. In collaboration with Steve Gill at the University of Rochester, we are analyzing three years of clinical data on S. aureus bacteremia in the Buffalo area and sequencing hundreds of bacteremia isolates of S. aureus to identify the genomic architectures associated with more severe complications and those associated with poor clinical outcomes. This work makes use of bioinformatics and database design, techniques that support my ongoing collaborations with other investigators on bioinformatics problems, particularly with Moraxella catarrhalis and Haemophilus influenzae. Prior to my studies in S. aureus, I conducted research on a fascinating pathogen, H. influenzae bio group aegyptius and Brazilian Purpuric Fever. Over that 10-year period my laboratory identified a unique epitope on a surface proteins associated with the disease. We were able to create the only isogenic mutant so far described with this pathogen that is highly refractory to genetic manipulation.
Drug abuse; Behavioral pharmacology; Neurobiology
I have two primary research interests. First, I use pharmacological approaches to seek novel therapeutics for pain. Pain is an agonizing symptom and disease that affects millions of people. Analgesics like opioids (e.g., OxyContin) are powerful for treating many pain conditions. However, opioids are not efficacious for some pain (e.g., neuropathic pain) and prolonged use of opioids has many side effects, including tolerance and dependence. The laboratory has been working on two interesting drug targets (imidazoline I2 receptors and GABAa receptors) for years in the hope that novel safer and effective analgesics can be developed from our preclinical research. Second, I am interested in pharmacotherapy of drug abuse. We use powerful behavioral pharmacological approaches, in animal models that are predictive of human stimulant abuse conditions, to study novel drug targets and evaluate potential pharmacotherapies against addictions to opioids, psychostimulants and nicotine. One unifying theme of the ongoing research in my laboratory is the application of receptor theory to the guidance and interpretation of the drug-receptor interactions in behaving animals.
I am an evolutionary biologist and vertebrate paleontologist with a research program focused on the auditory system of vertebrates, including fishes and human beings. My research interests span systematic interrelationships (phylogeny), functional anatomy and structural changes related to hearing impairment. My research goal is to understand the mechanisms underlying normal functions of vertebrates and the disorders and dysfunctions of human auditory structures; this understanding may lead to improved diagnosis, treatment and prevention of auditory disorders. Among organisms, there is a general correlation between form (anatomy) and function. I study the anatomical specializations for sound conduction and reception across vertebrate species. The evolutionary aspect of my research is centered on: 1.) exploring the utility of anatomical features for estimating phylogeny, 2.) describing important fossil taxa to provide deep-time longitudinal data and 3.) conducting integrated phylogenetic analyses using anatomical features and molecular data. I use Otophysi fishes as a model system, including suckers, carps, zebrafish and catfish--all fish with specialized sound-conduction apparatus. About one in eight people in the U.S. (age 12 and older) has some degree of hearing loss in both ears. My clinically oriented research is focused on the anatomical changes of the human auditory system, with regard to ontogeny and aging and the degree of hearing loss. I use methods in both descriptive and quantitative anatomy, including computed tomography, 3-D modeling and geometric morphometrics, to understand the normal function of human auditory system, along with its diseases and disorders. I also use zebrafish for experiments and computational simulations to test hypotheses on hearing loss.
Broadly, our focus is on developing novel nanomedicine approaches to meet unmet needs in treating, diagnosing or preventing disease. We strive to use good engineering principles to iteratively design, synthesize, characterize, test and validate next generation nanoparticles and biosensors with the ultimate goal of making a translational impact on improving human health. Developing safer, organic nanoparticles that will allow superior treatment options for cancer therapy is a major research thrust.
Genomics and proteomics; Protein Function and Structure; Proteins and metalloenzymes
The Malkowski Laboratory is focused on understanding the structure and function of integral membrane enzymes involved in the conversion of lipid precursors into potent bioactive signaling molecules. We utilize a myriad of methods and techniques to characterize these enzymes, including X-ray crystallography, electron spin resonance spectroscopy, protein chemistry, biochemistry, molecular biology, cell biology, and kinetics.
Apoptosis and cell death; Cell growth, differentiation and development; Cytoskeleton and cell motility; Immunology; Signal Transduction; Stem Cells
My independent research at The University at Buffalo focuses on targeting the mammary gland microenvironment by evaluating cellular and tissue responses during specific developmental windows of mammary gland remodeling including puberty, the period of hormonal withdrawal during estrous cycling, or post-lactational involution. My choice to focus on discrete times of development for chemopreventive intervention, rather than long-term (and often life-time) intervention, represents a unique approach of short-term exposure at critical points of mammary gland development. Our goal is to allow women to bypass the need for lifelong compliance to a chemopreventive diet or drug regimen in order to attain lifelong protection against breast cancer. Developmentally targeted dietary interventions being investigated in our lab include continuous administration of oral contraceptives, dietary exposure to conjugated linoleic acid, and ethanol.
Infectious Disease; Microbiology; Molecular and Cellular Biology; Molecular genetics; DNA Replication, Recombination and Repair; Virology; Genome Integrity
The major focus of my laboratory is in understanding the molecular machines that make up the DNA replication forks of the small human DNA viruses, polyoma- and papillomaviruses. Papillomaviruses and polyomaviruses are human pathogens; human papillomavirus (HPV) results in a vast number of human cancers, and the human polyomaviruses JC and BK cause serious disease and death in immunocompromised patients. Both viral systems provide important models for the study of human DNA replication mechanisms and have allowed for vital insights into eukaryotic DNA replication. The study of polyomavirus DNA replication led to the first identification of many cellular DNA replication complexes and processes; papillomavirus has provided the best structures and models to date of replicative hexameric DNA helicases and how they function. I typically train undergraduate, master’s and doctoral students and postdoctoral scholars, assistant research professors and laboratory technicians. My laboratory focuses on two primary areas. One is elucidating the dynamic protein-protein interactions that allow the series of enzymes required to replicate DNA to act in concert and in the correct sequence required to duplicate the genome. My laboratory has been at the forefront of identifying the interactions between the one critical HPV DNA replication protein, the origin-binding DNA helicase, E1, and cellular DNA replication proteins. Understanding these interactions and the roles they play in the HPV DNA replication process has helped our understanding of, and continues to lead to information that tells us more about how both viral and eukaryotic DNA replication forks function. In addition, as we identify protein-protein interactions between HPV E1 and cellular factors that are essential for HPV DNA synthesis, we will uncover potential targets for development of broad-range HPV antivirals that could act to block HPV replication. We recently obtained a large multilaboratory NIH research grant to investigate just this possibility for the interaction between HPV E1 and the human DNA replication protein, Topoisomerase I. The second primary area of investigation is elucidating how the cellular DNA damage response (DDR) pathways inhibit DNA replication when cells are subjected to DNA damage. For many years, the DDR field focused on the effects of DDR on the cell cycle kinases as the only method by which DNA replication was arrested. In the mid- to late-2000s, researchers recognized that in mammalian cells there is also a substantial (tenfold) inhibition of elongation of DNA replication following DDR. The mechanisms for this inhibition are unknown. Using both in vitro and cell-based simian virus 40 (SV40) DNA replication systems, we have shown that SV40 DNA replication is also shut down in response to DDR kinase pathways and that this is not based on cell cycle kinase action. Therefore, SV40 provides a useful model system for determining how elongation of DNA replication is inhibited by DDR. Furthermore, we have shown that in contrast HPV DNA replication does not respond to DDR, providing us an important control DNA replication system for these studies. (The lack of DDR arrest of HPV DNA replication likely explains why HPV integrates so readily into host cell chromosomes−an important step for HPV-induced carcinogenesis). Our studies on the DDR effect on polyoma and papilloma virus DNA replication will lead to insights into the effect of DDR on cellular DNA replication as well as an understanding of how HPV integrates into host cell chromosomes causing HPV-induced cancers.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Genomics and proteomics; Molecular genetics; Stem Cells; Transcription and Translation; Transgenic organisms; Vision science
We are interested in the fundamental mechanisms underlying the shift of cellular states from progenitors to fully functional mature cell types along individual cell lineages during development. We address this issue by studying cell fate specification and differentiation in the developing neural retina. Our efforts are on identifying key regulators, uncovering their roles in individual lineages, and understanding how they carry out these roles. Current projects are emphasized on how transcription factors influence the epigenetic landscape along the retinal ganglion cell lineage. We conduct our research using a combinatorial approach encompassing genetics, molecular biology, genomics, single cell analysis and bioinformatics.
Research in my laboratory focuses on nontypeable Haemophilus influenzae and Moraxella catarrhalis, important pathogens in otitis media and lower respiratory tract infections in adults with chronic obstructive pulmonary disease (COPD). A goal of work is to develop vaccine to prevent these infections. To that end, outer membrane proteins have been identified and are being evaluated as potential vaccine antigens. A COPD Study Clinic supported by a grant from the Department of Veteran Affairs has been running continuously since 1994. This prospective study follows adults with COPD during monthly clinic visits during which sputum and serum samples are collected. Bacterial isolates are recovered from sputum and are subjected to molecular typing. These studies are elucidating the dynamics of respiratory tract bacterial colonization. In addition, serum and sputum samples are being studied to learn about systemic and mucosal immune responses to bacterial pathogens.
Microbial Pathogenesis; Molecular and Cellular Biology; Gene Expression; Regulation of metabolism
The adaptive success of bacteria depends, in part, on the ability to sense and respond to their environment. Metals such as iron and manganese are important nutrients that can often be limiting, and therefore cellular metabolism must be modified to either scavenge the nutrients or use alternative processes that do not require the metal. Bradyrhizobium japonicum belongs to a group of related organisms that form a close or intracellular relationship with eukaryotes in a pathogenic or symbiotic context. This bacterium serves as a model to study related pathogens that are refractive to genetic and biochemical study. Our lab seeks to understand the mechanisms by which cells maintain iron homeostasis at the level of gene expression. We discovered the global transcriptional regulator Irr that controls iron-dependent processes. Irr is stable only under iron limitation, where it positively and negatively controls target genes. We are interested in understanding the mechanism of this conditional stability, how Irr regulates genes, and the functions of numerous genes under its control. Moreover, Irr integrates iron homeostasis with manganese metabolism, providing a link between the two nutrients. Identifying the Irr regulon and iron stimulon has given us important clues into how bacteria traffic iron into and out of the cell. Recent work suggests that B. japonicum not only adapts at the level of gene expression, but can mutate rapidly to accommodate new nutritional sources in the environment.
Dr. James M. O’Donnell was appointed as the eleventh Dean of the University at Buffalo School of Pharmacy and Pharmaceutical Sciences in October 2013. He is Professor of Pharmaceutical Sciences with a joint appointment as Professor of Pharmacology and Toxicology. He received his B.S. in Psychology from Carnegie Mellon University and Ph.D. in Pharmacological and Physiological Sciences from the University of Chicago; he completed postdoctoral training in Neuropsychopharmacology at the University of Pennsylvania. Prior to joining UB, he held research or faculty positions at Los Alamos National Laboratory, Louisiana State University, University of Tennessee, and West Virginia University; at WVU, he served as Associate Dean for Research in the School of Medicine and Assistant Vice President for Health Sciences Research. His research has focused on the relationship between the neurochemical and behavioral effects of drugs, primarily those used to treat neuropsychiatric illnesses. This has involved the study of noradrenergic mechanisms in the actions of antidepressant drugs and of cyclic nucleotide phosphodiesterases as potential targets for novel antidepressant, anxiolytic, and memory-enhancing drugs. This work has been supported by the NIH, primarily the National Institute of Mental Health, and has involved collaborations with scientists at other universities and biotech and pharmaceutical companies. Dr. O’Donnell has been active in the teaching of professional and graduate students in the areas of pharmacology and neuroscience and has provided research mentorship to undergraduate, graduate, and professional students, postdoctoral fellows, and junior faculty members. He served as Director of an NIGMS-supported, T32 predoctoral training grant at the interface of behavioral and biomedical sciences. He has served on NIH review panels in the neuroscience and drug discovery areas, including founding Chair of the Pathophysiological Basis of Mental Disorders and Addictions study section, and is Associate Editor for the Journal of Pharmacology and Experimental Therapeutics. He is a member of a number of scientific and professional societies, including the American Society for Pharmacology and Experimental Therapeutics and the Society for Neuroscience, is a Fellow of the American College of Neuropsychopharmacology, and chaired the Gordon Research Conference on Cyclic Nucleotide Phosphodiesterases.
BIG IDEAS ORIGINATING FROM SMALL (from BUFFALO Engineer 2018, “Engineering a healthier future. Engineering and medicine join forces to advance health care.” by Colleen Karuza; http://engineering.buffalo.edu/home/news/buffalo-engineer/feature-2.host.html/content/shared/engineering/home/buffalo-engineer/2018/features/engineering-a-healthier-future.detail.html) Kwang Oh is the director of the Sensors and MicroActuators Learning Lab, known as SMALL, which focuses on biomedical microfluidic devices, sensors and actuators. Kwang W. Oh is director of UB’s Sensors and MicroActuators Learning Lab (SMALL), a place, he says, where big things stem from micro- and nanotechnology, the science of manipulating matter at micro, molecular and atomic scales. Focusing on micro- and nanotechnology-based biological micro-electro-mechanical-systems (BioMEMS), Oh provides life scientists and physicians with the right tools “to solve problems in their own fields.” Oh came to UB in 2006 from Samsung, where he served as a member of its senior research and development team. “I was exposed to the very real problems facing the life sciences and subsequently developed a keen interest in applying engineering tools to the fields of biomedical research,” he said. At UB, he found other like-minded individuals who understood the important interplay of biology and technology. Oh, who holds appointments in the Departments of Electrical Engineering and Biomedical Engineering, explains that the science behind BioMEMS has played a significant role in ushering in recent advances in genomics, proteomics, single cell analysis and point-of-care diagnostics. BioMEMS research encompasses lab-on-a-chip technology, in which one or more laboratory functions are integrated onto a single chip using trace amounts of fluids, such as blood. Microfluidics forms the basis for much of Oh’s research, including the building of phantom models to test wearable medical devices. And what do Easter eggs have to offer bioengineering research? “Quite a lot,” says Oh. Inspired by the traditional Ukrainian Easter egg painting technique called “pysanky,” in which elaborate miniature wax designs are printed on the surface of an egg, “we applied a paraffin wax-based approach to low cost, rapid prototyping of microfluidic devices.” Oh is also investigating new ways to harness vacuum-driven energy to create more reliable microfluidic components, such as micropumps and microvalves, to facilitate lab-on-a-chip commercialization. “We have devised a manual, syringe-assisted, vacuum-driven micropump for plasma separation from a tiny drop of finger-prick blood and believe it has the potential to lead to practical biomedical lab-on-a-chip devices that can screen for glucose levels, cancer cells, viruses, DNA molecules and other applications.” HAPPY MARRIAGE Because technology provides the tools and biology the problems, the two should enjoy a happy marriage. Oh likes to share his favorite quote, which he came across in a journal article, with his colleagues and trainees. “It pretty much sums up the relationship our engineers have with clinicians and life scientists,” he says.
Ion channel kinetics and structure; Molecular and Cellular Biology; Neurobiology; Neuropharmacology
Our research program focuses on brain development, studying the development of the oligodendroglial and astroglial cell lineages in the central nervous system in normal, mutant and transgenic mice. The primary focus in the laboratory is on ion channels that regulate specification, migration and differentiation of these glial cells. The oligodendrocyte generates CNS myelin, which is essential for normal nervous system function. Thus, investigating the regulatory and signaling mechanisms that control its differentiation and the production of myelin is relevant to our understanding of brain development and of adult pathologies such as multiple sclerosis. We have recently discovered that voltage-gated Ca++ channels are necessary for normal myelination acting at multiple steps during oligodendrocyte progenitor cells (OPCs) development, however nothing is known about its role in demyelination or remyelination events. Our research aims to determine if voltage-gated Ca++ channels plays a functional role in myelin repair. Using transgenic mice and new imaging techniques we are testing the hypothesis that voltage-gated Ca++ entry promotes OPC survival and proliferation in the remyelinating adult brain. Therefore, this work is relevant to developing means to induce remyelination in myelin degenerative diseases and for myelin repair in damaged nervous tissue. Astrocytes are the most abundant cell of the human brain. They perform many functions, including biochemical support of endothelial cells that form the blood brain barrier, provision of nutrients to the nervous tissue and a role in the repair and scarring process of the brain and spinal cord following traumatic injuries. Our lab has made the novel finding of voltage-gated Ca++ channels function in astrocyte Ca++ homeostasis, and this has implications for plasticity in astrocyte development and for Ca++ regulation in general. We are testing the hypothesis that voltage-gated Ca++ entry plays a key role in astrocyte function and glial-neuronal interactions. We have generated a conditional knockout mice for voltage-gated Ca++ channels in astrocytes, these conditional knockout mice will allow the functional analysis of voltage-gated Ca++ channels in astroglia of the postnatal and adult brain. Analyzing such mice using a combination of behavioral, electrophysiological, imaging, and immunohistochemical techniques will provide new insights in our understanding of astroglial contribution to brain function. These projects have been supported for many years by grants from the NIH and the National Multiple Sclerosis Society.
Eukaryotic Pathogenesis; Gene Expression; Infectious Disease; Microbial Pathogenesis; Microbiology; RNA; Signal Transduction
There are estimated to be over one million species of fungi on the earth, yet very few of these species are capable of causing deadly systemic infections in humans. One of the major limiting factors for most fungi is their inability to grow at mammalian core body temperature. We utilize the fungal pathogen Cryptococcus neoformans var. grubii as a representative fungal pathogen to understand how these few fungi have adapted to growth at mammalian body temperature. C. neoformans is a worthy pathogen, as it is estimated to cause over 500,000 deaths from meningoencephalitis per year, primarily in Africa and Southeast Asia as an HIV/AIDS comorbidity. We use the temperature-limited Cryptococcus amylolentus as a comparator; it is an environmental strain that produces similar virulence factors to C. neoformans and is fully virulent in surrogate invertebrate hosts at permissive temperatures. We have discovered that host temperature adaptation in C. neoformans is accompanied by a reprogramming of gene expression at the level of messenger RNA (mRNA) stability. In response to temperature stress, C. neoformans rapidly degrades mRNAs that encode energy consuming machinery such as ribosomes. At the same time, it prioritizes the translation of stress-responsive mRNAs on existing ribosomes. Because mRNA synthesis and decay are coupled processes, we seek to identify the protein components of mRNA complexes that mediate the specificity of this decay process and posttranslational modifications, such as arginine methylation and phosphorylation, that modify their function. In addition, we are investigating the signaling pathways that accelerate or slow mRNA decay in response to specific environmental stimuli such as host temperature and nutrient deprivation. Finally, mRNA decay not only alters gene expression at the posttranscriptional level, but the degradation of abundant mRNAs during stress releases nucleotide intermediates that can be utilized by the stressed cell to promote genome stability. We are investigating the process of mRNA degradation as well as nucleotide metabolic pathways as drug targets in C. neoformans and other fungal pathogens. Our goal is to define the unique attributes of C. neoformans that confer pathogenicity and to identify potential targets for novel therapeutics. Each of my students has a project that contributes to the overall goals of my research team. Students in my laboratory work independently, though with frequent interaction with me regarding the direction of investigation and interpretation of data. Regular meetings allow us to provide input on each other’s projects. I expect my students to present their work at least once per year at a national or international meeting, and I expect them to do the bulk of the work in writing papers describing their findings for publication.
Behavioral pharmacology; Neurobiology; Neuropharmacology; Regulation of metabolism; Signal Transduction
Catecholamines such as dopamine and norepinephrine in the brain play important roles in a wide range of disparate physiological and behavioral processes such as reward, stress, sleep-wake cycle, attention and memory. The catecholamines are also well known for their treatment of neural disorders and many other diseases. Therefore, the examination of the catecholamines is of great importance not only in pharmaceutical formulations but also for diagnostic and clinical processes. The role and contribution of catecholaminergic innervation in the limbic system to biological functions and behavior are still poorly understood, however, due to the complicated functional heterogeneity, the small size of the limbic brain nuclei. In vivo and in vitro electrochemical measurement at microelectrodes has enabled direct monitoring of neuronal communication by chemical messengers in real time, which provides new insight into the way in which information is conveyed between neurons. Such information enables to study the basis for understanding the mechanisms that regulate it, the behavioral implications of the chemical messengers, and the factors regulate normal and altered chemical communication in various disease states (e.g. cardio vascular disease, degenerative nerve diseases, and drug addiction). My overall research focuses on two areas. Firstly, the design and implementation of development of new types of electrochemistry-based sensors and ancillary tools to monitor catecholamines and nonelectroactive neurochemicals in a chemically complex environment in the peripheral and central nervous systems of test animals. Secondly, application of the newly developed analytical techniques or existing methodologies for real-time monitoring of the neurochemicals i) to understand role of the neurochemicals in the brain in stress- and reward-related behaviors, ii) define and understand dysfunctions of the central and peripheral nervous systems in disease states by observing fundamental changes in neurochemical transmission in anesthetized and awakened animals.
Bioinformatics; Cell growth, differentiation and development; Neurobiology
My laboratory seeks to understand the transcriptional regulatory network governing the differentiation of oligodendrocytes and central nervous system (CNS) myelination, with the long-term goal of translating this knowledge into the treatment of demyelinating diseases. CNS myelination by oligodendrocytes is important not only for saltatory conduction of action potentials but also for trophic support of nerve axons. An improved understanding of how the differentiation of oligodendrocytes is regulated for CNS myelination should provide a firm basis on which to develop more effective therapeutics for demyelinating diseases. Toward this goal, we are currently pursuing two different research directions. The first is to elucidate the functional mechanism of Myrf, a key transcription factor for CNS myelination. Conditional knockout mice in which Myrf is knocked out in the oligodendrocyte lineage cells completely fail to develop CNS myelin and exhibit severe neurological symptoms, eventually prematurely dying. Recently, we and the Emery laboratory have independently made the surprising discovery that Myrf is generated as an integral membrane protein that is auto-cleaved by its ICA domain into two fragments. This discovery invokes a number of fundamental questions about how Myrf drives the differentiation of oligodendrocytes for CNS myelination. We employ both computational and experimental laboratory methodologies to elucidate the functional mechanism of Myrf. The second direction is to identify new transcription factors for CNS myelination. By taking advantage of our computational expertise, we have performed integrated computational analysis of functional genomics data that are publicly available to predict a number of new transcription factors for oligodendrocyte differentiation. We are currently characterizing them using primary oligodendrocyte cultures. Promising hits will be further analyzed by generating knockout mice to test for in vivo relevance.
Inherited Metabolic Disorders; Membrane Transport (Ion Transport); Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; Transgenic organisms; Vision science
Most physiological processes and numerous disease states influence or are influenced by pH. Even relatively small deviations in whole body pH can have devastating consequences for our health. Our bodies are subject to a constant challenge from dietary and metabolic acids, thus it is critical for the body to have mechanisms that tightly regulate pH. Blood plasma pH is maintained at a value close to 7.4, predominantly thanks to the buffering action of 24 mM bicarbonate (HCO3-). HCO3- neutralizes acid, generating carbon dioxide and water (HCO3- + H+ to CO2 + H2O), preventing lethal acidosis. I study the SLC4 family of membrane proteins that move acid/base equivalents across cell membranes. Notable members include  the Na/2HCO3 cotransporter NBCe1-A that reclaims HCO3- from filtered blood plasma in kidney tubules (preventing loss of vital plasma HCO3- to the urine),  NBCe1-B that promotes fluid removal from the corneal stroma (preventing corneal edema and vision loss),  the Cl-HCO3 exchanger AE1 that promotes O2-CO2 exchange in red blood cells, and  SLC4A11 that conducts H+ and promotes corneal clarity. Dysfunction of SLC4 family members is associated with renal tubular acidosis, blindness, cancer, deafness, epilepsy, and hypertension. Course Director for PGY405/505 (Cellular and Molecular Physiology) Course Co-Director for IMC512 (Renal Module)
Endocrinology; Molecular Basis of Disease; Neurobiology; Regulation of metabolism; Inherited Metabolic Disorders; Protein Function and Structure; Transgenic organisms
One research goal is to investigate the structure-function relationships and regulation of the human pyruvate dehydrogenase complex (PDC). We investigate the catalytic mechanism of the pyruvate dehydrogenase (PDH) component and its interactions with the dihydrolipoamide acetyltransferase (E2) component of PDC. We also determine the loci of interactions between PDH kinases (four PDK isoenzymes) and the lipoyl domains of E2. Using a PDC-knockout mouse line we investigate the importance of glucose metabolism as a source of energy for fetal development as well as the role of PDC in glucose-stimulated insulin secretion by pancreatic beta cells. Another research goal is to investigate diet-induced metabolic programming during early life. We investigate (i) the effects of an altered nutrition during the immediate postnatal life on development of adult-onset obesity and (ii) the effects of maternal obesity on fetal programming. Current research focuses on the role of the hypothalamic signaling pathways in rodents with diet-induced obesity and also in the progeny of obese mothers.
Cornea & External Disease; Ophthalmology; Vision science
As a specialist in cornea and external diseases of the eye, I treat a wide range of eye problems and perform a variety of surgical procedures including corneal transplantation, cataract surgery, conjunctival tumor surgery, and transplantation of the artificial cornea when standard corneal transplantation has failed. One of the most common reasons for corneal transplantation is corneal edema. Edema of the cornea develops from loss of corneal endothelial cells and causes irreversible vision loss in thousands of people yearly. Beyond surgical transplantation of the endothelial cell layer with human donor corneal tissue, no vision-restoring treatments are available. My research investigates the physiology regulating corneal hydration to advance future treatments for these patients. There are two main projects in my lab. The first looks at characterizing changes occurring in endothelial cell monolayer intercellular junctions and passive paracellular transport properties at low and high cell densities. Clinically, patients do not experience deterioration in vision or corneal edema until very low densities. The molecular basis for this observation is unknown. This project investigates changes in the apical junctional complex and monolayer permeability of the endothelium. The second project examines the mechanisms and regulation of active water transport out of the cornea. Using Ussing chamber physiology techniques, my lab is isolating the contributions and regulation of various ionic currents across the corneal endothelium with a focus on the contributions of potassium channels, bicarbonate and carbonic anhydrase inhibitors.
Neurological Surgery; Neurology
I have two major research interests: trophic factors as novel treatments for Parkinson‘s disease and CNS neoplasms. My lab has been characterizing the response to trauma in the caudate nucleus of parkinsonian animals. This work grew out of the observation that tissue grafts for parkinsonism lead to modest behavioral improvement, even when the graft did not survive. We have shown that several trophic factors are present in the caudate of rats after trauma which simulates graft placement. Both brain derived neurotrophic factor and ciliary neurotrophic factor are found in the caudate predictably at intervals after the surgical trauma. Further, there is at least one other, as yet unidentified factor present after trauma in the caudate. We have moved beyond identification to use of BDNF in parkinsonian models. Infusion of BDNF into the dopamine deficient caudate of a hemiparkinsonian rat leads to behavioral improvement and increased tyrosine hydroxylase (TH) staining, the rate limiting enzyme for dopamine synthesis. We are currently working on a delivery system to distribute BDNF, or other macromolecules like trophic factors, in the striatum of primates. The second area of active interest is in two forms of CNS neoplasia: leukemic meningitis and glioblastoma multiforme (GBM). We have created an animal model of leukemic meningitis in the athynic (nude) rat, using a human leukemic cell line. In collaboration with Dr. Steve Greenberg, we are working on a gene therapy approach using a white cell specific promoter and the viral thymidine kinase "suicide" enzyme. We are testing the constructs in vitro and in the nude rat model. In addition, we are working withDr. Greenberg to study the biology of GBM by transfecting human GBM cell lines with genes for vascular growth factors. Basic fibroblast growth factor, transforming growth factor beta, and endothelin-1 are currently being studied. The behavior of the transfected GBM cell lines are characterized in vitro, and after implantation into the frontal lobe of nude rats. By understanding how the transfected genes affect tumor growth, we hope to devise novel treatment strategies, potentially utilizing gene therapy.
Gene Expression; Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; Transcription and Translation
Our laboratory uses genetic, biochemical and molecular biological approaches to study the molecular mechanisms of eukaryotic transcription initiation and regulation. Studies in our laboratory utilizing both the budding yeast Saccharomyces cerevisiae and human cells have resulted in the identification and biochemical characterization of mutants of RNA polymerase II (RNAPII) and the general transcription factors TFIIB and TFIIF that coordinately affect transcription start site utilization and transcript elongation. These studies support a model where yeast and human TFIIF induce conformational changes in RNAPII that result in structural and functional changes in the polymerase active center.
Neurodegenerative disorders; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Neurobiology; Neuropharmacology; Protein Function and Structure; Signal Transduction
We investigate the activation mechanisms of fast neurotransmitter receptors. We seek to define the activation pathway, modulatory mechanisms and structure-function relationships of the N-methyl-D-aspartate (NMDA) receptor to better understand the roles played by this protein in the brain. NMDA receptors are the most abundant glutamate-stimulated, Ca2+-conducting ion channels in brain and spinal cord. They are the predominant molecular devices for controlling synaptic development and plasticity and govern memory and learning processes. Understanding the mechanisms that control their activity may lead to more effective strategies to treat neuropathies including stroke, neurodegenerative conditions, chronic pain and addiction as well as mental disorders such as schizophrenia and epilepsy.
Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Molecular and Cellular Biology; Protein Folding; Protein Function and Structure; Signal Transduction
Work in my lab seeks to elucidate the transduction mechanisms of ion channels involved in thermal sensation and pain, such as the heat-activated vanilloid receptors (TRPV1-4) and the cold-activated TRPM8 – the so-called thermal TRP channels. Expressed in peripheral afferent nerve endings, these channels function as an array of thermometers for sensing ambient temperature from noxious cold to noxious hot. While all proteins are thermally sensitive, thermal TRP channels are gated by temperature and possess unprecedentedly high temperature dependence. But the mechanisms of their temperature gating has remained mysterious, in contrast to our abundant knowledge on other types of ion channel gating (e.g. voltage or ligand-driven). Thermal TRP channels are also distinct for their polymodal responsiveness. TRPV1, for example, is responsive to heat, voltage, pH, capsaicin (i.e. the hot ingredient of chili peppers) among many other irritant compounds. The channels are thus informative for deciphering how biological proteins achieve multitasking. Thermal TRP channels also have receptor-like roles in mediating intracellular signaling. The calcium influx through the channels has potentially a broad spectrum of functional consequences, one of which is the desensitization of the channels themselves, a phenomenon that is believed to underlie peripheral analgesics. Our research is centered on problems like these, and we approach them by a combination of techniques such as recombinant mutagenesis, patch-clamp recording, fluorescence measurements, quantitative modeling, etc, which together allow us to draw insights into functions of the channels at mechanistic levels. Complementing our experimental studies, we are also interested in development of methodology to ever extend experimental resolutions. For example, to time-resolve temperature-dependent activation of thermal TRP channels, we have developed a laser diode-based temperature clamp apparatus, which achieves for the first time a submillisecond resolution (>105 oC/s) while capable of clamping temperature constant. For the past decade we have also been developing sophisticated algorithms for statistical analysis of single-molecule measurements such as single-channel patch-clamp recordings, which can help unravel the richness of data pertaining to molecular mechanisms at high resolutions. Together, these approaches provide us with unique abilities for in-depth studies of structure-mechanisms of ion channels.
Research focus areas: Proteomics and Pharmaceutical Analysis. Major research programs in the proteomic field involve i) high-resolution and large-scale expression profiling of pathological proteomes (e.g. for cardiovascular diseases, colon cancer and infectious diseases) for the discovery of disease/therapeutic biomarkers by gel-free LC/MS methods; ii) Sensitive identification, localization and quantification of post-translational modifications in complex proteomes, with the emphases on arginine methylation and phosphorylation. Novel anti-PTM-peptides capture procedure and alternating collision induced dissociation (CID)/electron transferring dissociation (ETD) are employed to obtain abundant PTM information; iii) targeted quantification of regulatory, marker proteins for clinical study. Dr. Qu‘s lab possesses many state-of-the-art LC/MS instruments, including a high resolution/accuracy LTQ/Orbitrap XL with ETD, a highly sensitive TSQ Quantum Ultra EMR triple-quadrupole instrument, two ultra-high pressure nano-LC systems, and several HPLC instruments for pre-fraction and ion chromatography. A number of key analytical advances have been developed by his lab that greatly enhanced the proteomic coverage, sensitivity and throughput for proteomic research. As for the Pharmaceutical Analysis of small-molecule drug/markers, Dr. Qu‘s lab is focusing on the ultra-sensitive quantifications of drug, metabolites and endogenous markers (e.g. corticosteroids, di-hydroxyl-vitamin D metabolites, androgens, etc.) using a novel combination of selective enrichment and micro- or nano- LC/MS.
Drug abuse; Apoptosis and cell death; Molecular and Cellular Biology; Neurobiology; Signal Transduction; Toxicology and Xenobiotics
My laboratory is focused on understanding the molecular and cellular actions of drugs of abuse such as ethanol and hallucinogens such as lysergic acid diethylamide (LSD). This information is a requisite step in the ultimate development of therapeutic interventions to alleviate the major healthcare and social burden associated with use and abuse of these drugs. In addition, these drugs provide an avenue to explore the basic workings of the brain under pathological conditions that are manifested as various psychiatric disorders. Previous studies, in collaboration with Dr JC Winter in the Dept of Pharmacology and Toxicology at UB, have investigated the roles of the various serotonin receptors subtypes and their associated signaling pathways as well as glutamatergic neurotransmission in the subjective effects of LSD-type hallucinogens. Our other studies have been aimed at understanding the adverse developmental effects of ethanol exposure that result in the fetal alcohol spectrum disorders with the fetal alcohol syndrome (FAS) as the most severe manifestation. Using zebrafish and neuronal cells in culture as model systems, my laboratory in collaboration with Dr CA Dlugos in the Dept of Pathology and Anatomical Sciences at UB have investigated the morphological and histological changes associated with ethanol exposure during different developmental stages as well as the mechanisms by which developmental ethanol exposure causes neuronal loss. Currently, we are investigating the neurotoxic interaction of ethanol with pesticides. Because of the wide-spread use of pesticides, people are continually exposed both voluntarily and involuntarily to an array of toxic chemicals. In addition, since consumption of alcohol is pervasive in our society with a very high prevalence of alcohol use and abuse, it is extremely likely that people with be co-exposed to both ethanol and pesticides. Because simultaneous or sequential exposure to multiple chemicals can dramatically modify the ensuing toxicological responses, we are using both in vitro (e.g., cells in culture) and in vivo (e.g., zebrafish) model systems to begin assessing the possible health risk of co-exposure to ethanol and pesticides. Using the herbicide paraquat, which is widely used throughout the world, as a test compound, we have found that ethanol synergistically increases the in vitro neurotoxicity of this pesticide. Our efforts are now aimed at ascertaining whether a similar interaction occurs in vivo as well as determining the molecular mechanism responsible for this synergistic neurotoxicity. Teaching is a naturally complement to research. Accordingly, I have also been engaged in efforts to both improve how we provide the knowledge base to our undergraduate, graduate, and professional students, and also how we help students learn to integrate and apply this information in problem-solving at the clinical and basic science levels. Efforts include: 1. using “clickers” in large class formats to assess student’s understanding of the material and well as provide each student instantaneous feedback for their own self-assessment; 2. using cases studies and a small group learning format; and 3. Having students write short grant proposals based upon the current literature as well as reviewing and critiquing their classmate’s proposals.
Eukaryotic Pathogenesis; Gene Expression; Genomics and proteomics; Infectious Disease; Microbial Pathogenesis; Microbiology; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; RNA
Trypanosoma brucei is a eukaryotic pathogen that causes human African trypanosomiasis, a disease that is invariably fatal if not treated. Essential and novel processes in this parasite may serve as starting platforms for new chemotherapeutics, which are urgently needed. Our laboratory combines biochemical, genetic, genomic and proteomic approaches toward understanding gene regulation and protein modification in this pathogenic eukaryote. One focus in my laboratory is RNA editing, a novel mechanism for regulating mitochondrial gene expression in which sequence information is added to mRNAs after transcription by specific insertion and deletion of uridine residues. RNA editing is essential for creating translatable open reading frames (ORFs). We are performing functional and biochemical characterization of the large, dynamic RNA-protein complex termed MRB1, which coordinates multiple aspects of the RNA editing process. A second focus is on regulating RNA stability and translational control in T. brucei, which constitute the major methods of gene regulation in this organism. We identified an RNA binding protein, DRBD18, that impacts the stabilities of hundreds of mRNAs. Our data support a model in which posttranslational modification of DRBD18 by arginine methylation acts as a switch to change DRBD18 from an mRNA destabilizer to an mRNA stabilizer by regulating specific protein-protein and protein-RNA interactions. We are testing this model in vitro and in vivo using reporter assays, in vivo protein-RNA cross-linking and protein-protein interaction assays. A third focus is on understanding the mechanisms by which protein arginine methylation modulates trypanosome biology. We performed a global proteomic analysis of the arginine methylome of T. brucei, identifying >1100 methylproteins spanning most cellular compartments and a wide array of functional classes. We are now analyzing novel mechanisms of protein arginine methyltransferase regulation and defining the physiological and molecular functions of arginine methylmarks on selected proteins. I foster a collaborative and flexible laboratory environment, and I encourage my students to explore the research topics that interest them.
Our research interests are broadly centered on studying the transcriptional regulatory mechanisms governing the development and differentiation of epithelial rich tissues. Our lab focuses on the lineage-specific master transcription factor, p63, which is a member of the p53 family of proteins. Using transgenic and knockout mouse models generated in the lab, we have demonstrated a critical role for p63 in directing stem/progenitor cell function and lineage choices, important for proper development of various tissues and organs including the skin and its appendages, the oral epithelium, and salivary glands. One current area of interest in the lab is to investigate the role of p63 in various facets of salivary gland development, stem cell renewal, organ homeostasis and repair. p63 is highly expressed in the myoepithelial cells of the salivary gland and in its absence, this organ fails to develop. We are currently using fluorescent reporters in transgenic mice to track, isolate and characterize the p63+ salivary gland stem cells. Our long term goals are to identify p63 driven signaling pathways and transcriptional networks that mediate stem/progenitor cell function in the salivary gland as well as the oral epithelium, using molecular, biochemical and genomic approaches.
Diagnostic Radiology; Neurological Surgery; Neuroradiology - Diagnostic Radiology; Neuroradiology - Radiology; Pediatric Radiology - Radiological Physics; Radiological Physics; Radiology; Vascular and Interventional Radiology
A SUNY Distinguished Professor & member of the UB faculty for more than 30 years, Dr. Rudin is a world-renowned expert in the field of medical physics. The quintessential interdisciplinary research scientist, Dr. Rudin is an international force in the development of a host of cutting-edge technology & methodology in the area of medical diagnostic & interventional imaging. He has won multiple awards for scientific excellence as well as awards for excellence in design, and is particularly well-known for his work in developing a high resolution x-ray imaging detectors, dose reduction methods, and endovascular devices such as asymmetric stents, work with major theoretical and clinical implications for medical physics, biomedical engineering, and diagnostic radiology, as well as an immediate impact upon patient diagnosis and care, particularly in case of brain and heart treatment. The caliber, significance, and innovation of his research are demonstrated by the numerous grants he has received from the NIH.
Periodontics; Operative Dentistry; Oral Biology; Pediatric Dentistry
Research in my laboratory encompasses the general area of oral infection and immunity with a major focus on adhesin-mediated interactions of oral bacteria with host salivary or cellular receptors. We investigate the glycoproteins in saliva that are recognized by lectin-like microbial adhesins. It is our long-term goal to better understand the modulating role of salivary glycoproteins in supporting tissue tropism of a benign commensal oral microflora to the human oral cavity and in host defense against pathogenic microorganisms. A more detailed description of our current research activities can be found on the following website:
Infectious Disease; Infectious Disease; Microbial Pathogenesis
I am an expert in infectious diseases, and I care for hospitalized patients at the Buffalo VA Medical Center (Buffalo VAMC). I have an active, nationally funded translational research program. My research focuses on Gram-negative bacilli (GNB), including Escherichia coli, Acinetobacter baumannii and a new hypervirulent variant of Klebsiella pneumoniae. These GNB cause infection in nearly every nonintestinal site in the body. The hypervirulent variant of K. pneumoniae is both fascinating and worrisome. Unlike its predecessors, it is capable of causing infection in young, healthy hosts and spreading nearly anywhere in the body from the initial infected site, including the eyes and brain. GNB-caused infections result in the loss of billions of health care dollars, millions of work days and hundreds of thousands of lives each year. GNB are becoming increasingly resistant to antibiotics, including strains that have become resistant to all available antibiotics. Unfortunately, there are virtually no new antimicrobial agents active against highly resistant GNB in the pharmaceutical “pipeline.” To address this formidable clinical challenge, my collaborators and I have increased our understanding of the bacterial factors that are critical for these GNB to cause infection. We use this information to develop vaccines that will prevent infection and antibodies that can be used to treat infection. My UB collaborators include Dr. Campagnari (microbiology), Dr. Gulick (structural biology) and Drs. Elkin and Zola (biomedical informatics). My research also involves identifying potential bacterial drug targets; this information will be used to develop new classes of antibiotics. I intermittently have students in my lab, and I participate in a grant designed to encourage medical students to become physician-scientists. I welcome interested students to contact me about conducting research with me. The Buffalo VAMC is the site of my clinical teaching. I teach first- and second-year medical students in lecture settings and small group sessions, including courses in lung respiration, musculoskeletal, renal and microbiology-immunology. Residents attend my grand rounds; I also teach fellows in all aspects of their training and mentor those who perform their research projects in my lab.
Cardiopulmonary physiology; Cytoskeleton and cell motility; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Molecular Basis of Disease; Signal Transduction
My research interests center on mechanical and electrical biophysics, from molecules to organs, and the development of new tools. And, in recent years I worked in transitional science; bringing basic science to the clinic and to industry. My basic research interests are on cell mechanics and the mechanisms by which mechanical forces are transduced into messages such as voltage and chemicals such as ATP and Ca2+. I discovered mechanosensitive ion channels in 1983. My methodology has included patch clamp, high resolution bright field light microscopy, low light fluorescence microscopy, high speed digital imaging, TIRF, digital image analysis, high voltage EM with tomography, Atomic Force Microscopy, molecular biology, natural product and recombinant protein biochemistry, NMR and microfabrication and microfluidics. We discovered the only known specific inhibitor of mechanosensitive ion channels and uncovered its remarkable mode action by using a combination of electrophysiology and chiral chemistry. We have demonstrated potential clinical applications of the peptide for cardiac arrhythmias, oncology, muscular dystrophy, and incontinence. We have developed many scientific tools. Recently we developed a sensor chip to measure cell volume in real time, and that is now entering production with Reichert Instruments of Buffalo. We also have an Small Business Innovation Research contract to develop a microfluidic, bipolar, temperature jump chip with ALA Scientific and developed a microfabricated Atomic Force Microscopy probe that is an order of magnitude faster and more stable than any commercial probes. We have made probe operable with two independent degrees of freedom on a standard Atomic Force Microscopy. This permits us to remove all drift and coherent noise by using one axis to measure the substrate position and the other the sample position. These probes are being produced by a new company in Buffalo, kBtwist. We have used the Atomic Force Microscope combined with electrophysiology to study the dynamics of single voltage dependent ion channels. This technique provides a resolution of >0.01nm in a kHz bandwidth. I have developed other hardware including the first automated microelectrode puller, a micron sized thermometer and heater and a high speed pressure servo. Some of these devices have been patented by the University of Buffalo and some are in current production. To analyze the reaction kinetics of single molecules, we developed and made publicly available (www.qub.buffalo.edu) a complete software package for Windows that does data acquisition and Markov likelihood analysis. The development was funded by the National Science Foundation, National Institutes of Health and Keck over the last fifteen years, and has been applied to ion channels, molecular motors and the even the sleep patterns of mice. We have taught at UB hands-on course to use the software, and the course was attended by an international group of academic scientists and students, government and industry.
My group performs research to understand, through multiscale modelling, how organismal metagenomes specify their behavior and characteristics in conjunction with their environments. We accomplish this by developing novel computational biology and bioinformatics algorithms for predicting protein and proteome structure, function, interaction, design and evolution. We apply these basic science techniques to important practical problems in medicine, genetic and genomic engineering and nanobiotechnology. I received the 2010 National Institutes of Health (NIH) Director‘s Pioneer Award to develop the Computational Analysis of Novel Drug Opportunities (CANDO) platform (http://protinfo.org/cando/) to repurpose drugs approved for other indications in a shotgun manner. Our integrated informatics platform determines interactions between and among all drugs and all protein structures to create compound-proteome interaction signatures. The compound-proteome interaction signatures are weighted using pharmacological, physiological and chemoinformatics data and compared and analyzed to predict the likelihood of the corresponding compounds being efficacious for all indications simultaneously, in effect inferring homology of drug behavior at a proteomic level. Using this approach, we have made predictions for all the indications that our library of drugs maps to, with benchmarking accuracies that are two orders of magnitude better than what is observed when using random controls. We have performed prospective in vitro validations of our predictions, demonstrating comparable or better inhibition than existing drugs approved for clinical use in indications such as dengue, dental caries, diabetes, hepatitis B, herpes, lupus, malaria and tuberculosis. Our approach may be generalized to compounds beyond those approved by the FDA, and it can as well consider mutations in protein structures to enable precision medicine. We have also applied our computational techniques to design peptides for vaccines, antibacterial activity and inorganic substrate adhesion and model the structures, functions and interactions of all tractable proteins encoded by several rice genomes. A consistent theme in our research is the combination of in virtuale simulation and homology inference, followed by in vitro and in vivo verification and application, directed toward holistic multiscale modelling of complex biological systems.
Biomedical Image Analysis; Biomedical Imaging; Bioinformatics
I have worked in three distinct research domains in my career: analytical statistical signal processing, experimental molecular imaging, and genomic data analysis. I collaborate with researchers from both academia and industry in multiple disciplines, including theoretical and applied physics, biochemistry, cell biology, molecular biology, and medicine. This multidisciplinary, cross-sector experience has given me unique skills and tools for successfully executing the goals of my laboratory. The major projects in my laboratory are focused on quantitative biomedical image processing and analysis. I am also interested in developing end-user biomedical software. This work will build on my previous research and expand into translational research that will directly support human health. At present, major projects in our lab are centered on developing computational methods to analyze histopathological images of the heterogeneous renal microscopic architecture. Using the developed computational tools, we are expecting to unearth early digital biomarkers of diabetic nephropathy (DN). Tools derived in our projects will allow modeling of clinical outcomes, such as end-stage renal disease and death, for DN patients and will also provide clinicians with invaluable information about their patient's expected disease trajectory and progression. Our laboratory is woven strongly into the Department of Pathology and Anatomical Sciences' innovative research and teaching directions that integrate anatomy, pathology, and data analysis. Departmental faculty members participate in both graduate biomedical and medical programs; as part of that effort, I seek motivated trainees/students to work in my research group to focus on our novel research direction. I believe that teaching and research greatly complement each other, and I emphasize equally teaching in the classroom and guiding students in my research lab.
Cell growth, differentiation and development; Cytoskeleton and cell motility; Stem Cells
Development of regenerative therapeutics involves understanding and application of molecular, cellular and tissue engineering principles. Integrated strategies include biomaterials, therapeutic molecules and stem cells to create bioengineered systems for regenerative medicine. Therefore, understanding fundamental interactions between different components and utilizing these concepts will provide tools to engineer tissue regeneration and develop treatment options for diseases. The translational aspect of regenerative medicine depends on proper integration of engineering and medicine. This hierarchical roadmap is tissue or disease specific and thus requires step-wise approaches. Our current goals are to develop strategies for therapeutic angiogenesis, soft and elastic tissue regeneration and delivery of drugs. We are interested to integrate the different components for effective therapeutic strategies
Oral Biology; Periodontics
RESEARCH ACTIVITIES Field of Specialization-Microbiology/Biochemistry Research Interests - Oral microbiology; Mechanisms of dental plaque formation; Saliva-bacterium interactions; Relationships between oral disease and systemic disease; respiratory infections; diabetes; salivary biomarkers of periodontal disease.
Cell growth, differentiation and development; DNA Replication, Recombination and Repair; Gene Expression; Molecular and Cellular Biology; Proteins and metalloenzymes; Signal Transduction; Transcription and Translation
The main goal of my research group is to understand the role of N-terminal methylation on human development and disease. I identified the first eukaryotic N-terminal methyltransferases, NRMT1 and NRMT2, and am now working to identify how these enzymes and this new type of methylation affect cancer development and ageing. Our laboratory has shown that NRMT1 functions as a tumor suppressor in mammary glands, and its loss sensitizes breast cancer cells to DNA damaging chemotherapeutics. We have also created the first NRMT1 knockout mouse and shown it to have developmental defects, as well as, exhibit phenotypes of premature ageing. Currently, we are working to understand the exact biochemical pathways that lead from loss of N-terminal methylation to these phenotypes. We are also studying how post-translational modifications on the N-terminus of proteins may interact and dictate protein function, similar to the post-translational modifications found on histone tails.
Internal Medicine - General
I am Research Associate Professor of Biomedical Informatics in the Department of Biomedical Informatics (BMI), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, SUNY (UB). Prior to joining BMI, I was a health sciences librarian focusing on instructing health care professionals and biomedical scientists of the importance of evidence-based practice, medical informatics, and lifelong learning. I taught learners and practitioners in all health care disciplines how to conduct quality searches of the literature, how to use information to create new knowledge, and how to value, use and recognize the expertise of the health sciences librarian. I have practiced a non-traditional form of librarianship as a result of my work at UB where I served as a faculty member embedded in the educational domain of the medical school; teaching medical students and residents, conducting research, serving on university committees, writing grants, and publishing the results of my work. As a hospital librarian I made a major commitment to developing educational programs for patients and families to ensure that they had access to quality, reliable, understandable health information. I was a member of a multidisciplinary team of health care professionals who taught refugee mothers from Somalia best practices for managing the health and wellness of their children. With funding from the National Network of Libraries of Medicine, Middle Atlantic Region, I created a program to teach diabetic patients with limited health literacy skills, how to find quality, reliable, and understandable health information to enable them to better manage their disease. I designed outreach programs for hospitalized patients to deliver information to their bedside, and also mailed material to patient’s homes. I persuaded the hospital’s CEO to provide space and support for a Wellness Center Library in the new vascular institute to meet the information needs of outpatients seeking day treatment for their disease. I will always apply the knowledge, skills and expertise that I have acquired throughout my career to my current appointment.
Multiple Sclerosis; Neurodegenerative disorders; Neuroimaging; Neurology; Neuroradiology - Radiology; Parkinson's; Radiological Physics; Radiology; Bioinformatics
Magnetic resonance imaging (MRI) is a unique technique for studying the human body since it is non-invasive, does not require ionizing radiation and offers a multiplicity of complementary tissue contrasts. My research seeks to explore the potential of MRI for clinical and pre-clinical imaging and to provide new and improved MRI technology. The goal of this endeavor is twofold: 1.) to contribute deeper insight into the etiology, pathogenesis and potential treatment of neurodegenerative diseases, and 2.) to give clinicians the ability to diagnose diseases earlier and monitor them more accurately. I am currently focusing on understanding MRI contrast mechanisms as well as on developing innovative imaging and reconstruction techniques that improve the sensitivity and specificity of MRI with respect to biophysical properties of brain tissue. Advancements in this field promise to have a substantial impact on our understanding of biophysical and morphological tissue alterations associated with neurological diseases and their treatment. We recently pioneered quantitative susceptibility mapping (QSM), a breakthrough in quantitative MRI. This technique allows for unique assessment of endogenous and exogenous magnetic particles in the human brain such as iron, calcium, myelin or contrast agents. The concept of QSM is fundamentally different from conventional MRI techniques as it involves solving for all imaging voxels simultaneously in large physically motivated equations, a so-called inverse problem. At the Buffalo Neuroimaging Analysis Center (BNAC), we use QSM to explore whether brain iron may serve as an early biomarker for diseases of the central nervous system such as multiple sclerosis and Parkinson’s disease. Other interesting applications of this technique we are investigating include differentiation between hemorrhages and calcifications, detection of demyelination and quantification of tissue oxygenation. I am fascinated by the synergies from combining physical expertise with high-level mathematical, numerical and engineering concepts to advance our understanding of the human brain. Consequently, my research activities are generally interdisciplinary and involve collaboration with clinicians, physicists, computer scientists, technicians and engineers. Student projects typically focus either on the application of techniques or on technical developments. Undergraduate, graduate and doctoral candidates from a variety of disciplines such as neuroscience, physics and mathematics work collaboratively in my lab.
Cardiology; Cardiovascular Disease; Internal Medicine; Radiology; Cardiopulmonary physiology; Autoimmunity; Cardiac pharmacology; Gene Expression; Immunology; Stem Cells
I am a cardiologist with specialized training in advanced cardiac imaging. I see outpatients at the Heart and Lung Center of Buffalo General Medicine Center (BGMC), and I care for inpatients through the cardiology consult and inpatient services at BGMC. As an advanced imaging cardiologist, I am responsible for developing and advancing the cardiac computed tomography (CT) and magnetic resonance imaging (MRI) programs at the Gates Vascular Institute (GVI) and providing these services to patients. These advanced, noninvasive imaging techniques allow physicians to perform in-depth, 3-D evaluation of the coronary tree, myocardium, heart valves, pericardium and great vessels. These imaging tools allow for the best possible diagnoses and care of patients. My research spans basic science, translational and clinical fields and combines the cross-discipline expertise on magnetic resonance (MR) technology with molecular biology. My overall goal is to study the consequences of ischemia-induced myocardial injury, with a focus on their therapeutic reversal. My research laboratory at UB’s Clinical and Translational Research Center (CTRC) is devoted to the development of novel time-and-tissue-targeted MRI methods for integrative understanding of cardiovascular pathophysiology in preclinical models. We have several interesting research projects, e.g., we have recently discovered that the presence of high-risk plaques in the carotid arteries predict future incidence of myocardial infarction and stroke. The results emphasize that the nature of atherosclerosis and the use of comprehensive non-invasive computed tomography angiography (CTA) will help identify patients who are at higher risk of developing ischemic stroke. These research results will help physicians employ early therapeutic strategies for these high-risk patients. I mentor medical students, residents and fellows both in clinical and research settings, and I precept cardiology fellows at the Heart and Lung Center at BGMC. In addition, I am deeply engaged in furthering the research and clinical education of our house staff. Our trainees have published their research in highly esteemed peer-reviewed journals, and many have routinely presented their work at national and international scientific conferences. I am committed to facilitating the career goals of my mentees while I continue to advance my own career as a clinician, researcher and mentor.
My research focuses on how prenatal environmental factors such as prenatal ethanol exposure and prenatal stress exposure alter various brain circuitries and how these effects lead to cognitive and behavioral deficits (impaired executive function, increased addiction risk, and anxiety) later in life. We also study how enriched postnatal environment can ameliorate these deficits. A wide array of techniques is used in my research, including cellular and system electrophysiology, immunocytochemistry, and various behavioral techniques. These techniques allow us to investigate changes in brain functions at cellular, circuitry, and behavioral levels. Our major discovery is that prenatal ethanol or prenatal stress exposure can lead to over-excitation of dopamine (DA) neurons located in the ventral tegmental area (VTA) and enhance their responses to drugs of abuse andcontribute to increased addiction risk. At this time, we are also investigating how prenatal ethanol exposure leads to impaired executive function and anixety-like behavior and the underlying mechanisms. My research contributes to the understanding of brain mechanisms mediating cognitive and behaviroal deficits in fetal alcohol spectrum disorders (FASD). These findings may lead to better treatment strategies of FASD.
I am the director of the Division of Cognitive and Behavioral Neurosciences in the Department of Neurology. I founded the Neurodiagnostic Laboratory at Buffalo General Hospital and I was the associate director of the Sleep Disorder Center of Western New York. I am a Diplomate in the American Board of Sleep Medicine and a Fellow in the American Psychological Association. My research is in the area of cognitive and behavioral neuroscience with particular interest in the neurophysiological basis of cognitive functioning, intellectual abilities, attention, and the role of sleep and sleep disorders, such as apnea, on neurocognitive functioning. The major methodological approach used in my laboratory is a combination of electrophysiological (mainly event-related brain potentials), neuropsychological, and other behavioral methods. Collaborative positron emission tomography (PET) and MRI studies have also been conducted in combination with electrophysiology. Both clinical and nonclinical populations are being studied. Populations studied have included infants, children, and adults, as well as animals. Recent work with clinical populations has focused on cognitive disturbances in autoimmune disorders such as Multiple Sclerosis and Systemic Lupus Erythematosus. Also, recent research has been directed at brain mechanisms of cognitive control such as conflict resolution and response inhibition. The development of novel electrophysiological markers of neural efficiency and cognitive function via state-of-the art dense electrophysiological techniques is also a focus of the research. In general, the research takes a systems approach to understanding cognitive functioning. Research and clinical training/teaching are important functions of the division. Over the years, our laboratory has mentored and trained undergraduate and graduate students, medical students, medical residents, and neuropsychology postdoctoral fellows/residents. Because of the scope of clinical and research areas housed within the Division, and the availability of collaborative possibilities, unique opportunities are present for training and for examining research questions in new and creative ways.
I am a clinical psychologist trained in the areas of clinical psychology and cognitive neuroscience. My clinical psychotherapy practice within the Department of Neurology focuses on the treatment of the psychological consequences that an individual experiences as a result of a neurological disorder or other chronic medically related problem. I use cognitive behavioral techniques to treat stress disorders, insomnia, depression and other emotional or behavioral problems that arise as a result of a medical condition. Cognitive behavioral therapy is a short-term and effective method that helps people identify and change thoughts, beliefs and attitudes that affect their feelings and behaviors. By restructuring patterns of thoughts, people are able to develop more effective coping skills, problem-solving strategies and emotional responses. I see patients in my office at the medical school on UB’s south campus. Neurologists or other health care professionals may refer patients to me or the patient may call my office directly using the contact information on my profile. I am the associate director of the Division of Cognitive and Behavioral Neurosciences in the Department of Neurology. My research interests are in the area of cognitive neuroscience. In our research laboratory, we apply electrophysiological (event-related brain potentials), neuropsychological and behavioral measures to the study of cognitive functions such as working memory/information processing speed, cognitive control and response inhibition. Specifically, the research areas include: working memory/processing speed deficits in systemic lupus erythematosus (SLE) and multiple sclerosis (MS); neuropsychological and electrophysiological aspects of attention, inhibitory control and other executive functions in individuals with post-traumatic stress disorder (PTSD); and the relationships among cognitive function, psychological function and quality of life in patients with SLE and MS. I mentor and train undergraduate and graduate students from the neuroscience program and UB’s Department of Psychology. Undergraduates and beginning graduate students learn about electrophysiological, behavioral, and cognitive testing methods, and they gain an understanding of the field of cognition and brain function. More advanced students conduct research projects in our laboratory, leading to undergraduate honors theses, master’s theses, and PhD dissertations.
Neurological Surgery; Neuroradiology
Dr. Adnan Siddiqui, MD, PhD, is a Professor of Neurosurgery and Radiology who joined UBNS in January 2007. He completed fellowship training in Interventional Neuroradiology, Cerebrovascular Surgery and Neurocritical Care from Thomas Jefferson University in Philadelphia. He completed his Neurosurgical residency at Upstate Medical University and received his PhD in Neuroscience from the University of Rochester and medical degree from Aga Khan University, Pakistan. Though Dr. Siddiqui is well trained in all general neurosurgical procedures, including brain tumor, spine and peripheral nerve surgery, because of specialized training, he has gravitated toward vascular diseases involving the brain and spinal cord. Dr. Siddiqui has special interest and expertise in the performance of complementary microsurgical, radiosurgical and endovascular techniques for the comprehensive management of cerebrovascular conditions. This spectrum of disease includes aneurysms and arteriovenous malformations, as well as dural, cavernous and spinal fistulae. He has special interests in acute stroke management with intra-arterial thrombolysis, as well as endovascular and microsurgical management of extracranial and intracranial vascular occlusive disease. Other clinical interests include endovascular management of intractable epistaxis; preoperative head, neck, and brain tumor embolization; resection of skull base tumors; endoscopic surgery for aneurysms and pituitary tumors; third ventriculostomy; and arachnoid cysts. The Neuroendovascular Research and Stroke Service is led by Dr. Siddiqui, who is proud to lead UB‘s Department of Neurosurgery, which was ranked 7th in academic impact in North America by the Journal of Neurosurgery. He serves as a reviewer for Stroke, Neurosurgery, Journal of Neurosurgery and Journal of Neurointerventional Surgery as well as many others. He has over 100 peer reviewed publications, more than 50 chapters and has been invited to more than 200 national and international lectureships. Dr. Siddiqui is currently a member of the Executive Council of the Joint Section of Cerebrovascular Surgery of the American Association of Neurological Surgery (AANS) and is Chairman of the Nominating Committee. He has served on Endovascular Task Force of AANS and been on multiple scientific committees on AANS, Society of Neurointerventional Surgery and the Congress of Neurological Surgeons. Dr. Siddiqui is married and has three children. He is a proud Buffalonian who is challenged and invigorated by taking care of neurosurgical patients and their families. He is grateful for the opportunity to work at the Gates Vascular Institute, a facility with some of the world‘s best technologies, where he and other experts can interact with leading researchers in order to make scientific advancements at the Toshiba Stroke & Vascular Research Center.
Genomics and proteomics; Neurobiology; Neurodegenerative disorders
My lab investigates the molecular control of cell fate and homeostasis of resident stem and progenitor cells in the human brain. Using a combination of multicolor cell sorting techniques and whole genome analysis, we are characterizing the signaling pathways which regulate the formation and fate of human oligodendrocyte progenitor cells. We are testing the functional significance of these pathways using both pharmacological and viral methods in culture and animal-based models of myelination and demyelination.
Behavioral pharmacology; Cardiac pharmacology; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Neurobiology; Neuropharmacology; Signal Transduction; Transgenic organisms
With over 400 genes coding for them in humans, ion channels play a significant role in most physiological functions. Drug-induced channel dysfunction often leads to a variety of disorders and results in significant incidence of serious injury and death. We investigate molecular mechanisms underlying neurodegenerative disorders and cardiac arrhythmias induced by ion channel dysfunction arising from genetic factors and/or drug interactions. The tools used for these investigations include genetic, electrophysiologic, pharmacologic, molecular and cell culturing methods. Preparations used for experiments include Drosophila as a genetic model system, and human cell lines expressing human ion channels that play an important role in critical-to-life functions including cardiac rhythm, respiration and the central nervous system.
Genomics and proteomics; Molecular and Cellular Biology; Gene Expression
My laboratory is interested in understanding the transcriptional control mechanisms that dictate epithelial cell development and differentiation. Specifically, we seek to understand the functional role of a p53-family member, p63 and Ets family of proteins in epithelial cells such as those of the skin and mammary glands. Towards this end, we have developed and characterized transgenic mice in which the normal expression pattern of these crucial factors is altered by both gain-of-function (Tet-inducible transgenic system) and loss-of-function (knockout) experiments. Our broad objectives are to elucidate the molecular mechanism by which transcription factors such as p63 and Ets proteins regulate their target genes and how such regulation of specific pathways dictate cell fate, development and differentiation. We utilize broad biochemical and genetic approaches, cell culture systems and state of the art genome-wide interrogation techniques to answer questions about differentiation of progenitor/stem populations and to examine molecular consequences of altered expression of transcription factors. These studies will not only help better understand the normal physiological processes but also lead to novel mechanistic insights into the pathophysiology of wide range of disease including cancer.
The laboratory seeks to understand information processing in the retina, a model for neural network analysis. Studies focus on the events that occur at synapses, with a particular emphasis on neurotransmitter-receptor interactions. Not only the neurotransmitter type but also the properties of receptor subtypes determines how neurons communicate. Our experiments investigate this linkage using electrophysiological, molecular and cell-imaging techniques. Subjects of current interest are: 1) synaptic communication by metabotropic receptors 2) properties of glycine receptors in retina and in expression systems; 3) acetylcholine-based signal transmission; 4) image-based analysis of retinal function. There is also a clinical application to the electroretinogram, a tool used by ophthalmologists to evaluate the health of the retina. We are able to use our knowledge of complex retinal circuits to improve the analytical potential of the electroretinogram. Transmitter-receptor interactions also form the basis for many pharmaceutical agents used to treat neurological problems. Therefore our retinal studies apply to the broad area of medicinal pharmacology.
Cell growth, differentiation and development; Gene Expression; Molecular and Cellular Biology; Neurobiology; Signal Transduction
The long term mission of my research has been to understand developmental and regenerative processes within the mammalian CNS. Towards these goals I have employed stereological and microscopic imaging techniques, stem cell cultures and in vivo models to analyze brain development, regenerative capacity, etiology of neurodevelopmental and neurodegenerative diseases. I have established a quantitative Neuroanatomy Stereology laboratory within a multi-disciplinary Molecular and Structural Neurobiology and Gene Therapy Program. Current projects: Developmental disorder- Schizophrenia The studies that I have been engaged in the last several years have addressed fundamental aspects of organismal development, their pathological disruptions and their targeting for regenerative medicine. With the advent of multicellular organisms, mechanisms emerged that imposed new controls which limited the natural propensity of organisms composed of single cells to proliferate, and to invade new locales, which ultimately results in the formation of tissues and organs. How such an immense task is accomplished has been largely unknown. Our collaborative studies have revealed a pan-ontogenic gene mechanism, Integrative Nuclear Fibroblast Growth Factor Receptor 1 (FGFR1) Signaling (INFS), which mediates global gene programing through the nuclear form of the FGFR1 receptor (nFGFR1) and its partner CREB Binding Protein, so as to assimilate signals from diverse signaling pathways. My work, which has contributed to these findings, has been focused on the role of INFS in cellular development. I have shown that INFS is central to the development of neural cells and that pluripotent ESC and multipotent NPCs can be programmed to exit from their cycles of self-renewal, and to undergo neuronal differentiation simply by transfecting a single protein, nFGFR1. Using viral and novel, nanotechnology based gene transfers, I have demonstrated that it is possible to reactivate developmental neurogenesis in adult brain by overexpressing nFGFR1 in brain stem/progenitor cells. We have shown that similar effects can be produced by small molecules that activate the INFS. These findings may revolutionize treatments of abnormal brain development, injury and neurodegenerative diseases by targeting INFS to reactivate brain neurogenesis. Schizophrenia (SZ) has been linked to the abnormal development of multiple neuronal systems, and to changes in genes within diverse ontogenic networks. Genetic studies have established a link between FGFs and nFGFR1 with these networks and SZ. nFGFR1 integrates signals from diverse SZ linked genes (>200 identified) and pathways[2-6] and controls developmental gene networks. By manipulating nFGFR1 function in the brain of transgenic mice I have established a model that mimics important characteristics of human schizophrenia: including its neurodevelopmental origin, the hypoplasia of DA neurons, increased numbers of immature neurons in cortex and hippocampus, disruption of brain cortical layers and connections, a delayed onset of behavioral symptoms, deficits across multiple domains of the disorder, and their correction by typical and atypical antipsychotics[6, 7]. To understand how SZ affects neural development, I have begun to generate induced pluripotent stem cells (iPSCs) using fibroblast of SZ patients with different genetic backgrounds. In my studies I employ 3-dimensional cultures of iPSCs, co-developmental grafting of the iPSCs neural progeny into murine brain, FISH (Fluorescent In Situ Hybridization), gene transfer and quantitative stereological analyses. I am testing how genomic dysregulation affects the developmental potential of schizophrenia NPCs (formation of 3D cortical organoids, in vivo development of grafted iPSCs) which may be normalized by correcting nFGFR1 and miRNA functions. In summary, my studies are aimed to develop to new treatments for Schizophrenia and other neurodevelopmental disorders including potential preventive therapies. Effect of maternal diet and metabolic deficits on brain development (collaboration with Dr. Mulchand Patel, Department of Biochemistry, UB) Approximately 36% of the adults in the US are classified as obese. Available evidence from epidemiological and animal studies indicate that altered nutritional experiences early in life can affect the development of obesity and associated metabolic diseases in adulthood and subsequently in the offspring of these people. Furthermore, there is an increased risk for mental health disorders that is associated with these conditions. Our studies show that an altered maternal environment in female rats produced by consuming a high fat (HF) or high sugar diet (HS) negatively impacts the development of brain stem cells and fetal brain circuitry in the offspring[8, 9]. Increased numbers of immature, underdeveloped neurons are found in the hypothalamus, which controls feeding behavior. Similar changes are found in areas of the cerebral cortex involved in other diverse behavioral functions. These changes reveal an alarming predisposition for neurodevelopmental abnormalities in the offspring of obese female rats. Blast induced brain injury and regeneration (collaboration with Dr. Richard Salvi, Department of Communicative Disorders and Sciences, UB) Sound blast induced brain injury is a major concern in military exposure to excessive noise. In mice exposed to the sound blast we found marked loss of myelinated fibers and neuronal apoptosis in brain cortex. These degenerative changes were accompanied by increased proliferation of brain neural progenitor cells in the subventricular zone of the lateral ventricles. Immunohistochemical and stereological analyses reveal that these initial changes are followed by the gradual reappearance of myelinated cortical fibers. This is accompanied by increased proliferation of oligodendrocytic progenitors. I found that these progenitors also differentiate to mature oligodendrocytes in brain cortex. Our findings show that the blast-induced activation of the brain neural stem/progenitor cells generates predominantly new oligodendrocytes. The capacity of these new cells to myelinate damaged and regenerating neurons will be addressed in my planned future investigation.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Gene therapy; Genome Integrity; Genomics and proteomics; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Signal Transduction; Stem Cells; Transcription and Translation
The long term mission of our laboratory, which I co-direct with Dr. Ewa Stachowiak, is to understand the principles governing molecular control of neural development, the implications for developmental- and aging-related diseases and the wide ranging effects on brain functions including behavior. The main achievement of our program has been the discovery of “Integrative Nuclear FGFR1 Signaling”, INFS a universal signaling mechanism which plays a novel integral role in cell development and complements other universal mechanisms such as mitotic cycle and pluripotency .Based on these revolutionary findings we have formulated a new theory called “Feed-Forward End-Gate Signaling” that explains how epigenetic factors either extracellular like neurotransmitters, hormonal or growth factors or intracellular signaling pathways control developmental gene programs and cellular development. This discovery is a product of our twenty-year multidisciplinary research that has been reported in several peer-reviewed papers in major journals including Proc. Natl. Acad. of Science (USA), Integrative Biology, Molecular Biology of the Cell, Journal of Cell Biology, Journal of Biological Chemistry, Journal of Physical Chemistry (etc.). In addition, we have applied this theory to analyze the etiology of neurodevelopmental /neurodegenerative disorders, and cancer in order to utilize it in new potential therapies. Towards these goals we have employed new technologies for an in vivo gene transfer, developed new transgenic mouse models for Schizophrenia and Parkinson-like diseases and established an interdisciplinary Molecular and Structural Neurobiology and Gene Therapy Program which has o engaged researchers from the different UB departments, other universities in the US as well as foreign institutions including Hannover Medical School (Germany), Gdansk Medical University, and Polish Academy of Science. Detailed research activities and future goals of our research program: 1. Molecular mechanisms controlling development of neural stem and related cells. In studying molecular mechanisms controlling development of neural stem and related cells we have established a novel universal signal transduction mechanism -Feed-Forward-And Gate network module that effects the differentiation of stem cells and neural progenitor cells. In the center of this module is the new gene-controlling mechanism "Integrative Nuclear Fibroblast Growth Factor Receptor-1 (FGFR1) Signaling" (INFS), which integrates diverse epigenetic signals and controls cell progression through ontogenic stages of proliferation, growth, and differentiation. We have shown that, Fibroblast Growth Factor Receptor-1 (FGFR1) a protein previously thought to be exclusively involved with transmembrane FGF signaling, resides in multiple subcellular compartments and is a multifactorial molecule that interacts with diverse cellular proteins In INFS, newly synthesized FGFR1 is released from the endoplasmic reticulum and translocates to the nucleus. In the nucleus, FGFR1 associates with nuclear matrix-attached centers of RNA transcription, interacts directly with transcriptional coactivators and kinases, activates transcription machinery and stimulates chromatin remodeling conducive of elevated gene activities. Our biophotonic experiments revealed that the gene activation by nuclear FGFR1 involves conversion of the immobile matrix-bound and the fast kinetic nucleoplasmic R1 into a slow kinetic chromatin binding population This conversion occurs through FGFR1’s interaction with the CBP and other nuclear proteins. The studies support a novel general mechanism in which gene activation is governed by FGFR1 protein movement and collisions with other proteins and nuclear structures. The INFS governs expression of developmentally regulated genes and plays a key role in the transition of proliferating neural stem cells into differentiating neurons development of glial cells, and can force neoplastic medulloblastoma and neuroblastoma cells to exit the cell cycle and enter a differentiation pathway and thus provides a new target for anti-cancer therapies. In our in vitro studies we are using different types of stem cells cultures, protein biochemistry, biophotonics analyses of protein mobility and interactions [Fluorescence Recovery after Photobleaching (FRAP), Fluorescence Loss In Photobleaching (FLIP), and Fluorescence Resonance Energy Transfer (FRET)] and diverse transcription systems to further elucidate the molecular circuits that control neural development. 2. Analyses of neural stem cell developmental mechanisms in vivo by direct gene transfer into the mammalian nervous system. An understanding of the mechanisms that control the transition of neural stem/progenitor cells (NS/PC) into functional neurons could potentially be used to recruit endogenously-produced NS/PC for neuronal replacement in a variety of neurological diseases. Using DNA-silica based nanoplexes and viral vectors we have shown that neuronogenesis can be effectively reinstated in the adult brain by genes engineered to target the Integrative Nuclear FGF Receptor-1 Signaling (INFS) pathway. Thus, targeting the INFS in brain stem cells via gene transfers or pharmacological activation may be used to induce selective neuronal differentiation, providing potentially revolutionizing treatment strategies of a broad range of neurological disorders. 3. Studies of brain development and neurodevelopmental diseases using transgenic mouse models. Our laboratory is also interested in the abnormal brain development affecting dopamine and other neurotransmitter neurons and its link to psychiatric diseases, including schizophrenia. Changes in FGF and its receptors FGFR1 have been found in the brains of schizophrenia and bipolar patients suggesting that impaired FGF signaling could underlie abnormal brain development and function associated with these disorders. Furthermore the INFS mechanism, integrates several pathways in which the schizophrenia-linked mutations have been reported. To test this hypothesis we engineered a new transgenic mouse model which results from hypoplastic development of DA neurons induced by a tyrosine kinase-deleted dominant negative mutant FGFR1(TK-) expressed in dopamine neurons. The structure and function of the brain’s DA neurons, serotonin neurons and other neuronal systems including cortical and hippocampal neurons are altered in TK- mice in a manner similar to that reported in patients with schizophrenia. Moreover, TK- mice express behavioral deficits that model schizophrenia-like positive symptoms (impaired sensory gaiting), negative symptoms (e.g. low social motivation), and impaired cognition ameliorated by typical or atypical antipsychotics. Supported by the grants from the pharmaceutical industry we are investigating new potential targets for anti-psychotic therapies using our preclinical FGFR1(TK-) transgenic model. Our future goals include in vivo gene therapy to verify whether neurodevelopmental pathologies may be reversed by targeting endogenous brain stem cells. Together with the other researchers of the SUNY Buffalo we have established Western New York Stem Cells Analysis Center in 2010 which includes Stem Cell Grafting and in vivo Analysis core which I direct. Together with Dr. E. Tzanakakis (UB Bioengineering Department) we have written book “ Stem cells- From Mechanisms to Technologies’ (World Scientific Publishing, 2011). Educational Activities and Teaching: I have participated together with the members of our neuroscience community in developing a new Graduate Program in Neuroscience at the SUNY, Buffalo. I am teaching neuroanatomy courses for dental students (ANA811) and for graduate students (NRS524). At present I participate in team-taught graduate courses in Neuroscience and Developmental Neuroscience (NRS 520, 521 and NRS 524). I am serving as a mentor for several undergraduate, graduate (masters and doctoral students) and postdoctoral fellows in the Neuroscience Program, Anatomy and Cell Biology Program and in the IGERT program in the Departments of Chemistry and Engineering. Additionally to mentoring master and Ph.D. students at the UB, I have helped to train graduate students in the University of Camerino (Italy) and Hannover Medical School (Germany). The works of our graduate students have been described in several publications.
Retroviruses comprise a large and diverse family of RNA viruses that can infect a variety of hosts and can lead to immune system dysfunction and cancer. The most well known member of this family is HIV (Human Immunodeficiency Virus), which is responsible for millions of deaths every year. Immune cells, such as CD4+ T cells, are the targets of HIV infection resulting in their subsequent destruction and the overall impairment of the immune system. As a result of the deterioration of the immune system, the host is unable to fight effectively infections and some other diseases. Opportunistic infections or cancers take advantage of the weakened host, which can prove to be lethal. Other members of the retrovirus family, Murine Leukemia Virus (MLV) and Mouse Mammary Tumor Virus (MMTV) are common pathogens of mice that are used in research to study the interplay between the host and retroviruses and have served as models for HIV and other human retroviruses. In the context of the constant struggle between host cells and pathogens, cells have developed early innate immune and cell-intrinsic strategies to counteract retroviruses. Therefore, retroviruses have developed a variety of sophisticated mechanisms to counteract cellular responses and allow for productive infections to occur. Due to the complexity of the antiviral immune response, a full understanding of host-pathogen interactions requires the integration of in vitro and in vivo data, where the role of cellular restriction factors and the innate immune response are examined in a living organism. Infections in mouse models have provided important and at times surprising insights into the relationship between hosts and pathogens. Thus one of the areas of focus for our lab will be the integration of in vivo and in vitro models to study the interaction of novel cellular host factors and retroviruses. HIV and other lentiviruses devote a relatively large portion of their genome to accessory proteins that counteract those cellular host factors. Understanding the function of these accessory proteins has provided insight into the intrinsic defenses utilized by the cell to block viral infections, as well as generated potential targets for antiviral interventions. However, there is no currently tractable in vivo model for studying cell host restriction factor/accessory protein interactions. Hence, the second major focus of our lab will be the development of in vivo models to examine the interplay between HIV accessory proteins and host cell intrinsic immunity.
Retina; Gene therapy; Neurodegenerative disorders; Pathophysiology; Protein Folding; Gene Expression; Signal Transduction
I am a Clinician Scientist working in the field of hereditary retinal and macular degenerations. I direct a regional referral service for these diseases at the Ross Eye Institute. My NIH- and VA-funded laboratory is focused on the development of gene-based therapeutics for hereditary retinal degenerations and common age-related macular degeneration.
Bioinformatics; Gene Expression; Genomics and proteomics
The recent development of high-throughput genomics technologies is revolutionizing many aspects of modern biology. However, the lack of computational algorithms and resources for analyzing massive data generated by these techniques has become a rate-limiting factor for scientific discoveries in biology research. In my laboratory, we study machine learning, data mining and bioinformatics and their applications to cancer informatics and metagenomics. Our work is based on solid mathematical and statistical theories. The main focus of our research is on developing advanced algorithms to help biologists keep pace with the unprecedented growth of genomics datasets available today and enable them to make full use of their massive, high-dimensional data for various biological enquiries. My research team is working on two major projects. The first is focused on metagenomics, currently funded by the National Institutes of Health (NIH), the National Science Foundation (NSF) and the Women’s Health Initiative. Our goal is to develop an integrated suite of computational and statistical algorithms to process millions or even hundreds of millions of microbial genome sequences to: 1) derive quantitative microbial signatures to characterize various infectious diseases, 2) interactively visualize the complex structure of a microbial community, 3) study microbe-microbe interactions and community dynamics and 4) identify novel species. We collaborate with researchers throughout the University at Buffalo, notably those in the School of Medicine and Biomedical Sciences, the School of Public Health and Health Professions and the College of Arts and Sciences. The second project focuses on cancer progression modeling. We use advanced computational algorithms to integrate clinical and genetics data from thousands of tumor and normal tissue samples to build a model of cancer progression. Delineating the disease dynamic process and identifying the molecular events that drive stepwise progression to malignancy would provide a wealth of new insights. Results of this work also would guide the development of improved cancer diagnostics, prognostics and targeted therapeutics. The bioinformatics algorithms and software developed in our lab have been used by more than 200 research institutes worldwide to process large, complex data sets that are core to a wide variety of biological and biomedical research.
DNA Replication, Recombination and Repair; Genome Integrity; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure
In my laboratory, we are interested in the general problem of maintaining genome stability. To this end, we focus on two distinct aspects of genome stability: 1) the roles of mismatch (MMR) proteins in multiple pathways for DNA repair and 2) the manner in which regulation of dNTP pools, through the regulation of ribonucleotide reductase (RNR) activity, impacts genome integrity. 1) MMR proteins recognize many different types of DNA lesions and then target the lesion for the appropriate repair pathway. We are interested in the mechanism(s) by which recognition of a lesion is translated into the appropriate DNA repair pathway, using the yeast Saccharomyces cerevisiae as a model system. Is it through differential protein-nucleic acid or protein-protein interactions? To address these questions as well as the regulation of DNA repair pathway selection, we use a combination of genetic, biochemical and biophysical approaches. 2) RNR activity modulates the level of dNTPs that are available in a cell at a given time. Higher levels of dNTPs lead to higher mutation rates. We are interested in the various ways in which misregulated dNTP pools might affect cellular metabolism and affect the stability of the genome.
DNA Replication, Recombination and Repair; Gene Expression; Genome Integrity; Microbiology; Molecular and Cellular Biology; Protein Function and Structure; Signal Transduction
We are interested in developing an integrated mechanistic view of how organisms coordinate the actions of their DNA replication machinery with those of other cellular factors involved in DNA repair and damage tolerance. Failure to properly coordinate these functions leads to mutations, genome instability, and in extreme cases, cell death. We utilize a combination of biochemical, biophysical, and genetic approaches to investigate the molecular mechanisms of DNA replication, DNA repair, and error-prone DNA damage tolerance functions in Escherichia coli. The primary mechanism for damage tolerance involves direct bypass of damaged bases in the DNA. This process is inherently error-prone, and is the basis for most mutations. Current efforts are focused on understanding the mechanisms by which the actions of high fidelity and error-prone lesion bypass DNA polymerases are coordinated with each other, as well as other proteins involved in DNA metabolism. Our goal in this work is to develop methods that enable us to control the fidelity of DNA repair for therapeutic gain. We are also interested in understanding the mechanisms that contribute to DNA mutagenesis in the opportunistic human pathogen, P. aeruginosa. P. aeruginosa is a particular problem for individuals afflicted with cystic fibrosis. Persistent colonization of cystic fibrosis airways with P. aeruginosa serves as a major source of morbidity and mortality for these patients. The ability of P. aeruginosa to persist in the airways relies in part on its ability to adapt to the continuously changing environment within the diseased airways. We are particularly interested in determining the contribution of mutagenesis and DNA repair to adaptive mutations that contribute to clonal expansion and pathoadaptation of P. aeruginosa during colonization of cystic fibrosis airways.
Alzheimer Disease / Memory Disorders; Neurology
I am a board-certified neurologist with specialty training in genetics and cognitive disorders, and I direct the Alzheimer’s Disease and Memory Disorders Center and Translational Genomics Research Laboratory, state-of-the-art facilities specializing in cognitive disorders. Our clinical mission is to provide compassionate, state-of-the-art care for patients and families affected by Alzheimer disease (AD) and other cognitive disorders. Our multidisciplinary approach includes a team of neurologists, neuropsychologists, neuroimagers, social workers and nurses dedicated to the needs of our patients and their caregivers. Our research mission is to employ genetic tools to identify novel risk factors and potential pathways that can be targeted with medications to prevent or modify the course of AD. Our focus is translating discoveries made in the laboratory into improved methods of disease prevention, diagnosis, and treatment. AD is a progressive neurodegenerative disease with high prevalence imposing a substantial public health problem. The heritability of AD is estimated at 60-80 %, forecasting a potential for using genetic biomarkers for risk stratification in the future. The main risk factor of late-onset AD is the APOE4 allele with a population attributable fraction of 0.2-0.3. Several large scale genome-wide association studies (GWAS) using high frequency variants identified nine additional loci with a combined population attributable fraction of 0.31. My laboratory focuses on finding the missing heritability using copy number variation as a genetic marker map. We perform CNV GWAS analysis on case-control datasets and quantitative endophenotypes, such as age at onset and biomarker data. We identified an olfactory receptor CNV association with age at onset of AD. Loss of smell sensation has been associated with AD and other neurodegenerative disorders; we are now applying a novel method, aCGH to study the olfactory subgenome in relation to smell sensation and cognition in normal aging individuals, patients affected by amnestic mild cognitive impairment and mild AD. This multicenter study is ongoing and is funded by the National Institute of Aging. In order to increase the power of association studies, we developed a method to use CNV as a genetic marker map and whole genome gene expression as quantitative trait loci within the same individual using post-mortem human temporal lobe tissue. In a pilot study, we identified a replicable 8 kb deletion association with AD upstream of CREB1. This small deletion harbors a PAX6 transcription factor binding site. We are pursuing iPSC technology to study the effect of this deletion on human neurons. We are also applying the same methodology on a larger set to identify additional signals. Our laboratory also collaborates with the Mendelian Project of Baylor College of Medicine in Houston, Texas. We are studying neurodegenerative dementias with Mendelian inheritance pattern by whole exome sequencing of informative pedigrees. My laboratory performs the data analysis and the follow-up studies for these mutations.
Cell growth, differentiation and development; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Signal Transduction; Inherited Metabolic Disorders; RNA
Regulation of Kidney Epithelial Cell Growth, Transport and Differentiation Our laboratory is investigating the molecular mechanisms by which hormones, growth factors and extracellular matrix proteins regulate kidney tubule epithelial cell growth and functional differentiation in vitro. An established canine kidney epithelial cell line, MDCK, and isolated "mutants" are currently being utilized to examine the actions of growth regulatory on the expression of several proteins including the Na+, K+-ATPase and laminin, a glycoprotein in the extracellular matrix. The effects of novel growth regulatory factors on the expression of proteins involved in gluconeogenesis, membrane transport, renal disease and growth control in primary renal cell cultures are being examined. Primary kidney epithelial cells differentiate into nephrons in a reconstituted extracellular matrix proteins is the subject of study.
Research in my laboratory is focused upon distinct projects in the fields of Behavioral Neuropharmacology and Neuroimaging of Addiction and Substance Abuse. Our research is based on the notion that there are specific genetic and epigenetic vulnerabilities that significantly contribute to Reward Deficiency Syndrome (RDS) of which addiction is a part of. My lab utilizes molecular, behavioral, and imaging (Positron Emission Tomography, MRI, CT, Autoradiograpjy) methods in animal models as well as how these models contribute to clinical data as part of several ongoing clinical translational studies.
Albert H. Titus is a professor in the Department of Biomedical Engineering at the University at Buffalo, the State University of New York. Prior to joining the faculty at Buffalo, he was an assistant professor at the Rochester Institute of Technology. He earned his Ph.D. from the Georgia Institute of Technology in 1997, and obtained his B.S. and M.S. degrees from the University at Buffalo in 1989 and 1991, respectively. His research interests include analog VLSI implementations of artificial vision, hardware and software artificial neural networks, optoelectronics and integrated sensor systems. Dr. Titus has numerous research grants from federal and private sources, including an NSF CAREER award. He has been a reviewer for many journals and conferences, and, he is a member of IEEE, INNS, ASEE and SPIE.
Immunopathology; Surgical Pathology; Renal Pathology
Patient care for a Pathologist is centered on assisting patients and clinicians in the understanding and the use of clinical laboratory data for the planning of therapeutic decisions. My personal specialty focus areas are in renal pathology, immunopathology, and urological pathology. I provide tissue biopsy and clinical laboratory diagnose , prognoses, and therapeutic advice to patients and clinicians on medical and surgical diseases of the kidney (including kidney transplants), bladder, prostate , and testis. These services include the interpretation of biopsies and pathology specimens, consultations on the ordering and/or the results of clinical laboratory lab tests. Raised in Philadelphia, PA I received my undergraduate education from LaSalle College in Philadelphia in 1973. I attended the University Of Pennsylvania School Of Medicine and received my MD in 1977. After finishing medical school I did an internship in Internal Medicine at Pennsylvania. I completed my Pathology Residency in anatomic and clinical pathology at the Hospital of the University of Pennsylvania in 1982. During that training I had special concentrations in immunology, HLA testing, and nephropathology. I was a Fellow in Surgical Pathology in 1982-1983. I joined the faculty in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania in 1983. In my first year of appointment I was given the opportunity to do a specially arranged fellowship with Dr Conrad Pirani in Nephropathology at Columbia University. At Penn I rose through the ranks to become Professor, Vice Chair for Anatomic Pathology-Hospital Services, and Interim Chair of the Department of Pathology and Laboratory Medicine My research interests are translational and have been focused in the domain of genitourinary pathology. Over the last decade I have had the great opportunity to work collaboratively with a group of image scientists in the development of quantitative image analysis tools tailored to the needs of the digital pathology community. Our vision is to create a new analytic paradigm fusing the data from the quantitative analysis of high resolution images with multidimensional molecular data. This “fused diagnostics” approach will support personalized predictive modeling of disease and its response to therapy. Our collaborative group is funded and is working hard to develop platforms which will support this new way of addressing complex multivariable testing. Over the years I have had the great good fortune to teach many classes of undergraduate medical students in nephropathology and genitourinary pathology. I have been Program Director of the Surgical Pathology and Immunopatholgy Fellowships at the Hospital of the University of Pennsylvania and instructed 56 Fellows. I have been a member of 9 PhD and 1 MS candidates’ thesis committees. I continue to instruct at the UME, GME, and Graduate student levels. I have been active in the work of many Pathology societies both as a speaker and in varied leadership roles. My volunteer work has been with the ACSP, USCAP, CAP, Pathology Informatics, ASIP, ICPI, and APC. I was a member of the ASCP Board of Directors for many years and rose through the leadership sequence to be elected ASCP President for 2010-2011. My society work has helped me understand both the challenges and the opportunities which face our profession in these times of great change. In 2011 I moved from Philadelphia to Buffalo to become Chair of Pathology and Anatomical Sciences at the University at Buffalo, State University of New York. I continue to maintain an active collaborative research program in image science and focus my efforts as Chair on building our clinical, educational, and research programs at UB. I am excited to be part of this great University which is on the rise.
Function and Structure
I am an integrative and evolutionary biologist, and my research focuses on the quantitative and functional anatomy and evolution of the mammalian craniodental system. One of the oldest endeavors in the study of gross anatomy is the exploration of the link between musculoskeletal structure and function. For centuries, scientists and artists alike have been digging into anatomical systems to draw connections between animal forms and the functional adaptations that allow some species to out-compete and out-survive others. Scientists’ and physicians’ understanding of current structure-function relationships can be improved by incorporating the long-term, evolutionary histories of anatomical systems. Research in my laboratory is focused on the macroevolutionary-scale patterns of structure-function relationships in mammals and other vertebrate groups. My model system of choice is the skull of carnivoramorphan mammals (dogs, cats, bears, hyenas and their living and extinct relatives). Despite the suggestion of a meat-eating lifestyle implied by the name of this mammal group, living carnivoramorphan species include not only specialists of vertebrate soft tissues, but others that are adapted to feed on insects, plants, fruits--or even bones. Projects in my lab include analysis of important variables such as diet, evolutionary relationships and non-masticatory functional constraints and their interplay on the structure and function of the skull as a feeding tool. I use methodologies such as landmark-based shape analysis (geometric morphometrics), model-based assessments of feeding performance (finite element analysis) as well as experiment-based model validation approaches and field-based and collection-based research on extinct mammal groups. I also use theoretical modeling approaches based on computed tomography (CT) to test functional optimality in skull structures of carnivoramorphans and primates (including humans). My goal is to develop a prototyping approach to better understand structure-function patterns of musculoskeletal systems. This will lead, eventually, to novel biomedical devices such as body implants and replacement body parts (e.g., artificial limbs) that benefit from a design approach informed by evolution. My lab is currently at full capacity for 2019-2020. Students interested in either the PhD or Master's programs are encouraged to check back in early 2020 for potential openings.
I am Clinical and Translational Pharm.D. Scientist and PI of R01AI111990 which seeks to investigate the Pharmacokinetics and Pharmacodynamics of Polymyxin Combinations. This R01 is interdisciplinary and blends diverse areas including microbiology and antimicrobial pharmacology with next generation sequencing and a number of infection models with an outstanding team of Pharm.D., M.D., and Ph.D. Co-Investigators. I am an internationally leading expert on antimicrobial pharmacology. In my early work in at Wayne State University, I completed new studies to optimize vancomycin dosing to combat heterogeneous resistance in Staphylococcus aureus by using PK/PD approaches to evaluate novel dosage regimens and antibiotic combinations. With the recent spread of multidrug-resistant Gram-negative bacteria, at the University at Buffalo, I developed an independent, federally funded research program, and expanded my research to refine exposure response approaches in a number of agents including colistin, polymyxin B, beta-lactams, and new combinations involving beta-lactam inhibitors against these very problematic pathogens. From 2008 to 2012, I have been a Co-investigator and PI of a subcontract at the University at Buffalo for R01A1079330 (PI Nation), a $2.3 million award from NIH. I am currently Principal Investigator of R01AI111990 a $4.4M grant which seeks to investigate the Pharmacokinetics and Pharmacodynamics of Polymyxin Combinations.
My research is aimed at determining how nerve cells establish appropriate connections during the development and regeneration of axonal connections. In recent years, my work has focused on the role of glutamate receptors in the development and regeneration of connections between the spinal cord and the muscle at the neuromuscular junction. Under normal conditions, each muscle fiber is innervated by a single nerve fiber, and Dr. Kirk Personius and I have demonstrated that glutamate receptors are integral to these processes. Until our work, this transmitter system had never been examined as a contributing factor. We now are exploring the mechanisms by which glutamate influences these important events. For many years prior to this work, I studied related questions in a very different system. My work focused on how early visual input influences the formation of topographic binocular connections in the midbrain optic tectum of the frog, Xenopus laevis. The relay for visual input from each eye to the ipsilateral tectum, is a tegmental structure called the nucleus isthmi. The axons from this structure are guided to the optic tectum by unknown non-visual processes, but within the tectum, their final connections are completely dependent on the visual input coming from the 2 eyes. Only if both eyes are open, optically normal and exposed simultaneously to patterned input, will the isthomotectal projection form a map of the ipsilateral eye‘s field which is in proper topographic registration with the contralateral eye‘s field. Absence of visual input during development prevents the isthmic axons from terminating in a topographically organized way, and strabismus causes the isthmic axons to form an orderly but abnormal map which is in register with the map from the misaligned eye. The NMDA (N-methyl-D-aspartate) glutamate receptor is essential to this process, and the transmitters acetylcholine and GABA also are being investigated for their roles in control of plasticity. The techniques that have been used in these experiments include extracellular electrophysiological recording methods, immunocytochemistry, electron microscopy, calcium imaging, receptor binding, whole-cell patch-clamping, knockdown techniques to control activation of transmitter systems, and anatomical tracing methods.
My research interests are developing methods for the analysis of medical images. My research focuses on creating parametric maps from post-reconstructed PET, SPECT, MRI, CT, and source localization EEG images. My current work focuses on improving parameter estimation using dynamic image noise reduction, segmentation algorithms, and the development of large image databases and specialized image search algorithms.
Synopsis Of Research: My research focuses on studying the diabetic related vascular complications, including diabetic retinopathy, diabetic vascular disease, insulin resistance and diabetic nephropathy. In addition to addressing mechanisms, our cellular and biochemical studies are meant to develop cures for diseases that affect the retina, peripheral vessel and kidney. 1.Diabetic retinopathy: Focusing on endoplasmic reticulum (ER) stress activation and interactions among ER stress, oxidative stress and inflammation in retina. 2.Peripheral vascular disease (PVD): Endothelial cells in the vascular system are especially vulnerable to hyperglycemic conditions. Exploring endothelial dysfunction in diabetic setting, would aid in the search for novel approaches in the prevention of diabetes vascular disease. 3.Diabetic nephropathy: Glomerular endothelial cells and podocytes are primary sites of injury resulting in chronic kidney disease in diabetes. We investigate the function of endogenous angiogenic inhibitors in regulation of renal cells in diabetic kidney. 4.Adipocyte and insulin resistance: Studying the function of PEDF in adipogenesis, provide pivotal information for understanding the mechanisms underlying the association of PEDF,obesity and insulin resistance. Selected Publications: 1.Boriushkin E, Wang JJ, Li J, Bhatta M, Zhang SX. p58(IPK) suppresses NLRP3 inflammasome activation and IL-1β production via inhibition of PKR in macrophages. Sci Rep. 2016 Apr 26;6:25013. doi: 10.1038/srep25013. PubMed PMID: 27113095; PubMed Central PMCID: PMC4845006. 2.Bhatta M, Ma JH, Wang JJ, Sakowski J, Zhang SX. Enhanced endoplasmic reticulum stress in bone marrow angiogenic progenitor cells in a mouse model of long-term experimental type 2 diabetes. Diabetologia. 2015 Sep;58(9):2181-90. doi: 10.1007/s00125-015-3643-3. Epub 2015 Jun 11. PubMed PMID: 26063198; PubMed Central PMCID: PMC4529381. 3.Gardner AW, Parker DE, Montgomery PS, Sosnowska D, Casanegra AI, Ungvari Z, Csiszar A, Zhang SX, Wang JJ, Sonntag WE. INFLUENCE OF DIABETES ON AMBULATION AND INFLAMMATION IN MEN AND WOMEN WITH SYMPTOMATIC PERIPHERAL ARTERY DISEASE. J Clin Transl Endocrinol. 2015 Dec 1;2(4):137-143. PubMed PMID: 26835254; PubMed Central PMCID: PMC4730895. 4.Zhang SX, Ma JH, Bhatta M, Fliesler SJ, Wang JJ. The unfolded protein response in retinal vascular diseases: implications and therapeutic potential beyond protein folding. Prog Retin Eye Res. 2015 Mar;45:111-31. doi: 10.1016/j.preteyeres.2014.12.001. Epub 2014 Dec 18. Review. PubMed PMID: 25529848; PubMed Central PMCID: PMC4339403. 5.Chen C, Cano M, Wang JJ, Li J, Huang C, Yu Q, Herbert TP, Handa JT, Zhang SX. Role of unfolded protein response dysregulation in oxidative injury of retinal pigment epithelial cells. Antioxid Redox Signal. 2014 May 10;20(14):2091-106. doi: 10.1089/ars.2013.5240. Epub 2013 Dec 17. PubMed PMID: 24053669; PubMed Central PMCID: PMC3995121 6.Zhang SX, Sanders E, Wang JJ. Endoplasmic reticulum stress and inflammation: mechanisms and implications in diabetic retinopathy. J Ocul Biol Dis Infor. 2011 Jun;4(1-2):51-61. doi: 10.1007/s12177-011-9075-5. Epub 2012 Jan 18. PubMed PMID: 23330021; PubMed Central PMCID: PMC3342410. 7.Wang M, Wang JJ, Li J, Park K, Qian X, Ma JX, Zhang SX. Pigment epithelium-derived factor suppresses adipogenesis via inhibition of the MAPK/ERK pathway in 3T3-L1 preadipocytes. Am J Physiol Endocrinol Metab. 2009 Dec;297(6):E1378-87. doi: 10.1152/ajpendo.00252.2009. Epub 2009 Oct PubMed PMID: 19808909; PubMed Central PMCID: PMC2793046. 8.Wang JJ, Zhang SX, Mott R, Knapp RR, Cao W, Lau K, Ma JX. Salutary effect of pigment epithelium-derived factor in diabetic nephropathy: evidence for antifibrogenic activities. Diabetes. 2006 Jun;55(6):1678-85. PubMed PMID: 16731830. See more publications on http://www.ncbi.nlm.nih.gov/sites/myncbi/1heXcsvGDSdAl/bibliography/41170057/public/?sort=date&direction=ascending.
Cardiology; Cardiovascular Disease; Stem Cells
My research program is focused on the investigation of mechanisms underlying functional and structural cardiac remodeling in heart disease, as well as novel therapeutic interventions to prevent or reverse left ventricular dysfunction caused by myocardial ischemia and hemodynamic overload. These studies generally utilize non-invasive advanced cardiovascular imaging techniques and invasive hemodynamic assessment to assess cardiac performance in vivo, along with ex vivo analysis of myocardial tissue to examine cellular and molecular mechanisms underlying observed changes in physiological function.
My research interests include all aspects of brain function although I generally look at issues that involve brain dysfunction. Traumatic brain injury including mild tbi (concussion) fascinate me. My research career has centered on the treatment of individuals living with the effects of traumatic rain injury (TBI). This has included research on family coping strategies and rehabilitation outcomes. One of my current research interests is focused onmild TBI. I am the director of research for the University concussion clinic. We have been evaluating the impact of concussion on the physiology of the patient and looking for treatments that help to ameliorate the long-term effects. We have recently evaluated the use of the Balke treadmill test to evaluate readiness to return toplay. We found this procedure to be reliable and safe and extremely useful in differential diagnosis of post concussion syndrome. We have also just completed a fMRI pilot study of individuals with PCS and found that as patients improved in their symptoms and physiologic response to treatment, that their brains were more efficient metabolically. They used less energy to accomplish the same task and the foci of activity were more consistent with the demands of the task. We also found that subjects that followed an exercise regime recovered quicker and had brain function more closely aligned with the normal controls. My second research focus relates to emotion recognition, emotion expression and emotion regulation in individuals with moderate to severe TBI. Approximately one third of individuals with moderate to severe TBA will have impaired abilities in emotion regulation. We have developed a computer based treatment protocol that was found effective in a pilot study. This protocol is currently being evaluated in a RCT that is multi-site and multi-national.
Infectious Disease; Microbiology; Microbial Pathogenesis; Molecular and Cellular Biology; Gene Expression; Transcription and Translation; Protein Function and Structure; RNA; Eukaryotic Pathogenesis
In my laboratory, we use molecular biological and biochemical approaches to study Trypanosoma brucei, the causative agent of African sleeping sickness, and Trypanosoma cruzi, which causes Chagas disease in South and Central America. Treatment for these diseases is severely limited due to increasing drug resistance and lack of available drugs. The goal of our work is to discover and exploit critical events that occur in the parasite life cycle that may be used to prevent growth or transmission of the parasite. The major project in my laboratory examines the ribosome, the complex molecular machine that drives protein synthesis. While many features of the ribosome and its assembly pathway are conserved in the parasites we study, we have identified features that are very different from the human host. Our laboratory discovered a pair of trypanosome-specific RNA binding proteins, P34 and P37, that are part of a unique preribosomal complex that is essential for ribosomal biogenesis and survival of trypanosomes. This may suggest that the interaction of these proteins with other components of the ribosomal assembly pathway can be developed as targets for chemotherapy. We are developing a high-throughput screen for small molecules that disrupt the complex in trypanosomes and do not harm the human host. My team and I also collaborate with Dr. Joachim Frank at Columbia University on a project to examine the structure of the ribosome and intermediates in the pathway of assembly using cryo-electron microscopy (cryo-EM). These experiments will provide important information about the unique features of the structure and function of the trypanosome ribosome and further our discovery of potential drug targets. In addition, we continue in a long-standing collaboration with Dr. Beatriz Garat at the Universidad de la Républica in Uruguay, examining both DNA and RNA binding proteins which regulate gene expression in Trypanosoma cruzi. The balance of graduate, undergraduate and medical students and postdoctoral researchers I mentor changes from year to year, though the international quality I strive to maintain has distinguished my laboratory for years: I enjoy having students from around the world as part of my research team. I am the course director for, and lecture in Critical Analysis and Eukaryotic Pathogens. I am also the course director for Eukaryotic Gene Expression and the co-course director for Molecular Parasitology.
Immunology; Infectious Disease
The focus of my laboratory is to understand regulatory mechanisms during infection and autoimmunity at mucosal sites, particularly within the gastrointestinal tract. The adult human intestine alone contains up to 100 trillion micro-organisms─and no other tissue is submitted to a greater level of antigenic pressure than the gut, which is constantly exposed to food and environmental antigens and the threat of invasion by pathogens. At birth, for example, the human gastrointestinal tract undergoes a massive exposure to these antigens, and throughout the average human life there are multiple instances of the remodeling of the gut flora following infection. All these occurrences impose a unique challenge to the gastrointestinal environment. In response, to maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. Several subsets of immune cells with immune modulatory function reside within the gastrointestinal tract. Specifically, we study Foxp3 expressing regulatory T cells (Tregs), which play a central role in controlling intestinal homeostasis. Recent studies have demonstrated that the ability of Tregs to control defined polarized settings requires plasticity, the acquisition of characteristics specific to the glycoprotein CD4+ T effector subsets. Such adaptation comes with an inherent cost, however; as my research team and other researchers have demonstrated, in extreme instances of inflammation such adaptation can actually be associated with the expression of pro-inflammatory effector cytokines (i.e., interferon gamma and interleukin 17A). We recently identified GATA3, the canonical Th2 transcription factor, as a critical regulator of Treg adaptation during inflammation in tissues. Our goal is to understand how GATA3 regulates this and to identify other factors involved in Treg adaptation during inflammation. Our laboratory employs natural enteric parasitic infections of mice and the T cell dependent model of colitis to decipher both the environmental cues and cell- intrinsic requirements for Treg cell plasticity, stability and function at mucosal sites. The ultimate goal of our research is to clarify the pathogenesis of inflammatory bowel disease (IBD) and develop novel treatment modalities for patients.
Neurology; Neuromuscular Disorders
I arrived in January 2012 to assume the role of Chair of the Department of Neurology at Univ. at Buffalo School of Medicine and Biomedical Sciences, the State University of New York. Prior to that time, I served as Professor of Neurology at University of Texas Southwestern Medical School in Dallas, Texas. In September 2004, I was named to the Dr. Bob and Jean Smith Foundation Distinguished Chair in Neuromuscular Disease Research. I also served as Co-Director of the Muscular Dystrophy Association Clinics and Director of the Myasthenia Gravis and Peripheral Neuropathy Clinics at UT Southwestern and was the Clinical Vice Chair for the department in Dallas. My interests in neuromuscular medicine are wide but have mainly focused on myasthenia gravis and other disorders of neuromuscular transmission, as well as peripheral neuropathies. I am board certified both in neurology and neuromuscular medicine. I am also board certified in neurophysiology, and I perform electromyography and nerve conduction studies and monitor intraoperative evoked potentials for spine surgeries and other operative cases. My main research interests include idiopathic and immune-mediated peripheral neuropathies and myasthenia gravis. My research has been sponsored by the National Institute of Health/NINDS, Muscular Dystrophy Association, Myasthenia Gravis Foundation of America, and Food and Drug Administration. I remain actively involved in the training of younger physicians, and have directed neuromuscular medicine and clinical neurophysiology fellowships and neurology residency training programs in the past.
Developmental Neurology; Neurology
My laboratory has a longstanding interest in myelin and its diseases. Myelin surrounds large axons and permits rapid conduction of signals. It is formed by oligodendrocytes in the central nervous system, and Schwann cells in the peripheral nervous system. During development, these cells migrate with the axons that they will myelinate, and depend on those same axons for appropriate signals to survive and differentiate. Myelin-forming glia coordinately express a unique set of genes encoding myelin structural proteins, and enzymes that synthesize myelin lipids-this coordination is in large part transcriptionally-mediated. Given the unique three dimensional transformation of the cell required for myelination, many of the involved proteins include adhesion among their functions. Therefore, our projects include studies of transcriptional regulation, axonal signals to myelinating glia, the role of adhesion in myelination and the characterization of animal models of human demyelinating diseases.
The main focus of my research is to develop novel optical and ultrasonic imaging techniques to meet needs in cancer and neurological research. In my lab, students will have the opportunities to be trained in optical and ultrasonic engineering, be involved with preclinical and clinical imaging studies, and be collaborating with chemists, physicians and neurologists in Western New York and Ontario Canada.
Neurodegenerative disorders; Pathophysiology; Cytoskeleton and cell motility; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Neuropharmacology; Signal Transduction
Synaptic Mechanisms of Mental Health and Disorders Our research goal is to understand the synaptic action of various neuromodulators that are linked to mental health and illness, including dopamine, stress hormones, and disease susceptibility genes. Specifically, we try to understand how these neuromodulators regulate glutamatergic and GABAergic transmission in prefrontal cortex (PFC), which is important for emotional and cognitive control under normal conditions. We also try to understand how the aberrant action of neuromodulators under pathological conditions leads to dysregulation of synaptic transmission in PFC, which is commonly implicated in brain disorders. The major techniques used in our studies include: • whole-cell patch-clamp recordings of synaptic currents, • viral-based in vivo gene transfer, • biochemical and immunocytochemical detection of synaptic proteins, • molecular analysis of genetic and epigenetic alterations, • chemogenetic manipulation of neuronal circuits, • behavioral assays. By integrating the multidisciplinary approaches, we have been investigating the unique and convergent actions of neuromodulators on postsynaptic glutamate and GABAA receptors, and their contributions to the pathogenesis of a variety of mental disorders, including ADHD, autism, schizophrenia, depression, PTSD and Alzheimer‘s disease.
My research focus is on advancing the technology of nuclear medicine imaging, a non-invasive, in vivo, functional molecular imaging modality. The goal is to provide accurate and cost effective imaging solutions to support biomedical applications such as early disease diagnosis, early treatment assessment, and short development cycle of new drugs. My research projects are in three areas. One is about improving the quality of nuclear medicine imaging systems, namely positron emission tomography (PET), and single photon emission computed tomography (SPECT), through accurate modeling, and therefore compensating, of the physical factors involved in the radiation signal detection process. One example is that we developed a probability density function based PET system matrix derivation method, and implemented the method through Monte Carlo simulation on UB’s high performance computing clusters. The method provides a systematic and comprehensive scheme for modeling any nuclear medicine imaging systems. The second area of my research is about developing multiple imaging functionalities on top of existing nuclear medicine imaging systems or on a platform with shared system components. The advantage of this strategy includes the synergetic benefits of a multiple modality system, and the cost saving from sharing resources. An example project is that we developed an add-on SPECT (single photon emission computed tomography) on an existing PET (positron emission tomography) scanner. This allows the PET detector system be used for performing both PET and SPECT imaging studies with the combined libraries of PET and SPECT radiopharmaceuticals. My third research area is about developing effective imaging protocols for applications using animal PET and other imaging systems. This usually involves collaboration with researchers in other specialties.
Leslie Ying received her B. Eng. in Electronics Engineering from Tsinghua University, China in 1997 and both her M.S. and Ph.D. in Electrical Engineering from the University of Illinois at Urbana - Champaign in 1999 and 2003, respectively. She is now an Associate Professor of Biomedical Engineering and Electrical Engineering at SUNY-Buffalo. Before joining SUNY-Buffalo, she was on faculty at the Department of Electrical Engineering and Computer Science, the University of Wisconsin - Milwaukee. Her research interests include magnetic resonance imaging, compressed sensing, and image reconstruction. She received a CAREER award from the National Science Foundation in 2009. She was elected as an AdCom member of the IEEE Engineering in Medicine and Biology Society in 2012. She is a Deputy Editor of Magnetic Resonance in Medicine and a senior member of IEEE.
Ophthalmology; Retina; Apoptosis and cell death; Gene Expression; Gene therapy; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Protein Folding; Regulation of metabolism; Signal Transduction; Vision science
The research in my lab has focused on two main areas: 1). molecular mechanisms of inflammation, angiogenesis, vascular and neuronal degeneration in retinal diseases; 2). potential roles of angiogenic inhibitors in obesity, insulin resistance and diabetes. The first line of research centers on gene regulation and signal transduction pathways underlying the neurovascular injury in diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration. In recent years, we are focusing our efforts on the function and mechanism of the UPR signaling in normal and diseased retinal cells. The latter one combines basic and clinical research to study biomarkers and mechanism of type 2 diabetes. 1. ER stress and the UPR signaling in retinal neurovascular injury and diabetic retinopathy. The endoplasmic reticulum (ER) is the primary site for protein synthesis and folding. Failure of this machinery to fold newly synthesized proteins presents unique dangers to the cell and is termed “ER stress.” In response to the stress, cells have evolved an intricate set of signaling pathways named the unfolded protein response (UPR) to restore the ER homeostasis. In addition, the UPR is known to regulates many genes involved in important physiological processes to modulate cell activity and cell fate. The project in my laboratory is aimed to understand the role of ER stress and the UPR in retinal vascular endothelial cell dysfunction and neuronal degeneration in diabetic retinopathy. Our previous work has implicated several key UPR branches such as IRE-XBP1 and ATF4-CHOP in retinal inflammation and vasculopathy in diabetes. Currently, we are employing integrated genetic tools and animal models to study the function of UPR genes in the retina and to dicepher the molecular links between the UPR signaling and inflammatory pathways in retinal cells. Findings from these studies are anticipated to identify novel therapeutic targets and develop new treatments for diabetic retinopathy. 2. Mechanisms and potential therapies for RPE death in age-related macular degeneration. The retinal pigment epithelium (RPE) plays an essential role in maintaining the normal structure and function of photoreceptors. RPE dysfunction and cell death is a hallmark pathological characteristic of age-related macular degeneration (AMD), a disease that accounts for the majority of vision impairment in the elderly. Using transgenic mouse models, we discovered that the transcription factor XBP1 is a critical regulator of oxidative stress and cell survival in RPE cells. Genetic depletion or inhibition of XBP1 sensitizes the RPE to stress resulting in cell death. Our ongoing studies focus on identifying the target genes of XBP1 in RPE cells through which the protein regulates cell survival. We are also investigating if these proteins could offer potential salutary effects to protect RPE cells from oxidative injury and degeneration in disease conditions such as AMD. 3. Roles and mechanisms of angiogenic/anti-angiogenic factors in obesity, insulin resistance and diabetes. Obesity, insulin resistance and Type 2 diabetes are clustered as the most important metabolic disorders, substantially increasing morbidity and impairing quality of life. Excess body fat mass, particularly visceral fat, leads to dysregulation of adipokines (proteins secreted from fat cells), resulting in higher risk of cardiovascular diseases. Our recent findings indicate that angiogenic/anti-angiogenic factors are associated with obesity, diabetes and diabetic complications. For example, pigment epithelium-derived factor (PEDF), a major angiogenic inhibitor, is an active player in adipose tissue formation, insulin resistance and vascular function. In the future, we hope to futher understand the functions and mechanisms of these proteins in lipid metabolism and adiposity. In collaboration with a number of clinical investigators, we are exploring the physiological application of these factors as novel biomarkers and therapeutic targets in the diagnosis and treatment of diabetes, metabolic disorders and peripheral vascular diseases.
Research interests include: Developing advanced biofabrication technologies such as organ-on-chip models for disease modeling and drug screening; 3D bioprinting of large-size, vascularized tissues for repairing injured soft tissues; Fibrosis disease and anti-fibrosis therapies; Study of cell and tissue mechanics using novel experimental and computational tools.
Neurology; Neuroradiology - Radiology; Vascular and Interventional Radiology; Parkinson's; Multiple Sclerosis; Alzheimer Disease / Memory Disorders; Developmental Neurology; General Neurology; Neurodegenerative disorders; Neuroimaging
I direct the Buffalo Neuroimaging Analysis Center (BNAC) and have established the center as a world leader in performing quantitative MRI analysis in neurodegenerative disorders. I also direct the Translational Imaging Center at UB’s Clinical Translational Research Center (CTRC). I strive to extend the boundaries of current knowledge about neurological diseases and disorders through innovative imaging research techniques and the application of bioinformatics resources. My efforts are directed toward advancing technical, basic and translational research at UB which will, in turn, advance patient care. I have secured more than $30 million in research grants for collaborative research projects involving UB investigators as well as national and international collaborators. My research interests include structural and functional quantitative MRI analysis for humans and animals, including lesion/tumor identification and segmentation; perfusion and dynamic contrast-enhanced (DCE) mapping and quantification; fluid flow quantification; functional MRI analysis; diffusion tensor reconstruction and tractography; voxel-wise mapping and image-based group statistical analysis; longitudinal change analysis and tissue/pathology/structure volumetry. I study the application of these techniques in healthy individuals and in patients with various disease states such as multiple sclerosis (MS), stroke, Alzheimer’s disease, Parkinson’s disease, epilepsy, systemic lupus erythematosus and traumatic brain injury. I also concentrate on therapeutic interventions, including therapy directed toward assessing neuroprotective efforts in neurodegenerative disorders as well as the venous function, genetic and neuroepidemiology fields of these diseases. I direct the neurology resident research program. Over a period of two years, I guide third- and fourth-year medical residents through a rigorous assigned scientific research project that is a critical, required part of their training. In addition, I mentor and supervise undergraduate, master’s and doctoral students and MRI fellows. In this role, I help to educate these trainees on clinical MRI use as well as neuroimaging analysis. I also oversee students and fellows conducting research in neurological disorders. One of the most rewarding experiences in my career is helping young physicians and researchers start successful clinical or research careers.