This directory lists MSTP faculty from the Jacobs School of Medicine and
Biomedical Sciences and from the School of Dental
Medicine’s Department of Oral
Biology. For faculty in departments from our affiliated schools
and institutes, see the list at the right.
-Research is focused on the clinical aspects of microbiology. Molecular and immunologic methods are used to detect and characterize emerging and reemerging microbial agents of infection, particularly Chlamydia and Mycobacterium tuberculosis. The role of cytomegalovirus infection in transplantation has been extensively studied. Additional interests include the changing patterns of resistance of gram-negative and gram-positive microorganisms to antimicrobial agents. Methods for detecting and monitoring the susceptibility (resistance) of these organisms in conventional and automated systems have been developed and are the basis for ongoing studies. The Erie County Medical Center Healthcare Network‘s Department of Laboratory Medicine is a comprehensive, full-range service and reference laboratory dedicated to provide state-of-the-art quality and timely testing results to area physicians and health care providers. Licensed and accredited by several agencies and organizations including the New York State Department of Health and the Joint Commission on Hospital Accreditation, the Department of Laboratory Medicine used quality assurance, quality management and continuous quality improvement to strengthen service delivery and ensure superlative laboratory testing. Accuracy, timeliness, and convenience are the major components of these programs. The professional staff of the Department of Laboratory Medicine has been awarded Certificates of Qualification from the New York State Department of Health. Many are board certified in their medical specialty and have State University of New York at Buffalo School of Medicine and Biomedical Sciences academic appointments in the departments of medicine, microbiology, biochemistry, pathology and clinical laboratory sciences.
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.
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, receptor activation and ion permeation. Our research combines the approaches of pharmacology, enzymology, structural and molecular biology, electrophysiology, and mathematical modeling. Our primary goal is to understand the molecular operation of these membrane proteins in the context of their physiological roles. We also study the biophysical basis of ion channel diseases. To see a movie of AChR gating, click here
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
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.
Drug abuse; Circadian Rhythm/Chronobiology; Gene Expression; Molecular and Cellular Biology; 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.
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.
Reproductive Endocrinology; Apoptosis and cell death; Cell growth, differentiation and development; Endocrinology; Gene Expression; Molecular genetics; Signal Transduction; Toxicology and Xenobiotics; Vitamins and Trace Nutrient
I am an Associate Professor in the Department of Pharmacology & Toxicology of the School of Medicine and Biomedical Sciences. I have a secondary appointment as Adjunct Associate Professor in the Department of Oral Biology in the School of Dental Medicine. My research interests focus on the study of how hormones and nutrients affect cell growth, differentiation, and survival. I study these processes in bone osteoblasts and breast normal epithelial cells as well as cancers of both tissues. I have discovered how natural estrogens as well as dietary phytochemicals sustain osteoblast longevity and contribute to bone growth. In collaboration with Dr Atif Awad of the University at Buffalo School of Public Health, I have identified dietary factors that inhibit the growth of cancers of the prostate and breast. We have published primary research papers, significant review articles, and two books entitled "Nutrition and Cancer Prevention" and Adipose Tissue and Inflammation".
Bioinformatics; Genomics and proteomics; Molecular and Cellular Biology; Molecular genetics; Gene Expression; Transcription and Translation
Our research group is interested in how regulatory proteins are targeted to the correct DNA binding sites at the correct time. Transcription factors are directed to their genomic targets by DNA sequence, local chromatin structure, and protein-protein interactions. These modulators of transcription factor binding are not independent but function both cooperatively and competitively to regulate where transcription factors bind. Understanding how these modulators affect transcription factor binding in vivo remains a major unsolved biological problem. We use the model organism Saccharomyces cerevisiae to address the disconnect between the presence of the correct DNA binding sequence and true regulatory protein binding, integrating both experimental and computational approaches to: i) investigate transcription factor binding in response to environmental stress, ii) identify and characterize the mechanisms directing transcription factor target selection, and iii) and develop bioinformatics tools to analyze and interpret ChIP-seq experiments and chromatin structural patterns.
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.
Molecular and Cellular Biology; Neurobiology; Neuropharmacology
The goal of my research is the elucidation of the role of brainstem systems in motivated behaviors. My current focus is the function of neuropeptide systems, specifically urotensin II (UII). Ultimately I would like to exploit this system to better treat people with neuropsychiatric 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) Establish the contribution of cholinergic PPT to Parkinsonism-related behaviors: 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). Similarly, the collection of deficits found after non-selective manipulations of the PPT overlap with that of Parkinson’s Disease [e.g. reduced prepulse inhibition, impaired attention, cognitive deficits, sleep disturbances]. Traditional dopamine-depletion models do not produce similar sensorimotor and cognitive deficits. Therefore, PPT lesions as an adjunct or stand alone preclinical models of Parkinsonism may be useful in identifying non-dopaminergic pharmacotherapeutics. We are pursuing further studies utilizing our selective cholinergic depletion and a viral-mediated tauopathy method with support from the CurePSP Foundation.
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.
Experiments focus on the dynamics of microtubule assembly in spindles during the process of meiosis using live imaging of 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.
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 I have worked on include a computer-guided program of instruction 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 Diseases; 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.
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.
Apoptosis and cell death; Molecular Basis of Disease; Neurobiology
Professional Summary: The research in my laboratory has been focused on the effects of chronic ethanol abuse on aging neurons and the effects of ethanol on development of neuronal systems. These investigations are associated with major socioeconomic issues that will become more pronounced with time. For example, alcoholism in the elderly will become more pronounced as the alcohol-drinking baby boomer generation reaches old age. In addition, alcohol consumption during pregnancy remains the number one cause of mental retardation in the western world. In our aging and alcohol studies, extensive investigation of the Purkinje neuron (PN) of the cerebellar cortex have demonstrated that dendritic regression accompanies chronic ethanol consumption in aging Fischer 344 rats. Dendritic regression in PN alters synaptic transmission from the cerebellum, the major brain center for coordination. Further ethanol-induced alteration of regressing dendrites include dilation of the smooth endoplasmic reticulum (SER), a major calcium homeostatic component, and the formation of degenerating structures in dendrites of Purkinje neurons following chronic ethanol consumption in aging rats. These morphologic changes have been recently shown to be accompanied by decreased levels of the SERCA 2b pump which pumps calcium back into the SER following an action potential. Homeostasis between uptake and release of calcium from the SER is essential for cell health as uncontrolled release of calcium results in activation of a myriad of cellular pathways and cell death. Current investigations in the laboratory as focusing on the role ATF6 and caspase 12, both residents of the SER, in the development of ethanol-induced SER stress as a result of chronic ethanol consumption. Future investigations will include other ethanol-induced alterations to calcium homeostatic systems and the role of ethanol-induced alterations in epigenetics in decreases in calcium buffering mechanisms. The fetal alcohol study has focused on the effects of ethanol on the eye and the heart in the zebrafish model. Zebrafish are good models for developmental studies because they are transparent the short developmental period of three days between fertilization and hatching. Early investigations in collaboration with Dr. Richard Rabin established that the zebrafish was sensitive to ethanol and that the sensitivity was dose and strain dependent. Later studies focused on morphological and pharmacological assessment of ethanol-induced alterations to the heart and eye using pharmacologically relevant effects of ethanol. Current plans include focus on determining the mechanisms of ethanol’s actions on retinal ganglion cells and dopaminergic centers in the zebrafish.
Digital Pathology; Image Analysis; Machine Learning; Quantitative Histology
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.
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 neuronal development and in specific types of cancer. These projects utilize a wide range of techniques and involve, in the case of the latter focus, a collaboration with investigators at Roswell Park Cancer Institute to develop a protein kinase-targeted therapy for prostate cancer.
Cell growth, differentiation and development; Molecular Basis of Disease; Proteins and metalloenzymes; Gene Expression; Inherited Metabolic Disorders; Protein Function and Structure; Cell Cycle
Protein Methylation in Growth and Differentiation. Protein methylation was recently found by systems biology approaches to play a major role in regulating yeast cell growth. Consistent with this finding, we found that disruption of the gene encoding S-adenosylhomocysteine (SAH1) hydrolase markedly inhibited growth. S-adenosylmethionine (SAM) is the universal methyl donor,and SAH1 is the product of all methyltransferase(MTase) reactions.The SAH1 disruption leads to a 50% decrease in protein synthesis which,in turn leads to major decreases in the levels of Cln3p.Unexpectedly,when cells were transfected with a modified gene for Cln3 ,that desreased its rate of degradation,growth rates were normal.This result was unexpected because the basic defect of lacking SAH1 remained.We are currently testing the hypothesis that normal rates of growth are due to increased gene expression for multiple enzymes known to be involved in Met and SAM synthesis. We are also identifying substrates for specific MTases in yeast. Copper deficiency is known to affect brain development, and Menkes disease is fatal due to impaired brain development from low brain copper. A reduction in (SAH1) levels, as occurs in copper deficiency, may affect brain development by inhibiting protein methylation.We demonstrated that inhibiting SAH1 maredly inhibited development of two nerve cell models.
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.
Implant Dentistry; Oral Biology; Periodontics
-Research is directed towards understanding the mechanisms of virulence of mucosal pathogens. Adherence is a critical first step in the pathogenesis of mucosal diseases, as it is important in interactions with mammalian cells, they can activate macrophages and play a role in invasion of epithelial cells. The molecular basis of adherence and fimbrial and nonfimbrial-associated adhesins are investigated. Adhesin for binding of pathogenic bacteria to mucous-covered surfaces have been studied at the molecular level. Studies of fimbrial adhesins of P. gingivalis have shown that protein interactions with salivary components are critical. Investigation of binding domains of fimbrial adhesin-associated proteins, their synthesis, and assembly, and expression of this organelle are among our current projects. We are exploring the immunogenicity of adhesins as well, using synthetic peptides in order to evaluate their usefulness as vaccines. Studies of S. gordonii as a vector for these vaccines is proceeding through genetic engineering of strains and testing in animal and human studies. Infections and Chronic Diseases. We are studying the systemic factors which alter the risk for periodontal disease, one of the most common infections of humans. Diabetes mellitus, osteopenia, stress and inadequate coping and smoking are conditions which increase susceptibility to periodontal infections. More recently, we have studied the effect of periodontal infections as they increase the risk for heart disease including myocardial infarction; and decreased glycemic control in diabetics. In vitro studies of molecular and cellular mechanisms, animal models and human epidemiologic studies, as well as randomized clinical trials are all underway to study the interdependence of periodontal infections and heart disease, diabetes and osteoporosis.
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.
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.
Mucociliiary Transport; Cell growth, differentiation and development; Cytoskeleton and cell motility; Molecular and Cellular Biology; Signal Transduction
Our lab is involved in two major projects: 1) Cell motility research – mucociliary transport. We have developed a series of real “models” or simplifications of the respiratory mucociliary epithelium (primary cultures, isolated epithelial sheets, isolated ciliated cells, demembranated and MgATP-reactivated cell models, and isolated, demembranated and reactivated ciliary axonemes) that allow one to study mucociliary transport at number of levels of organization. We have studied these models using biochemical methods, stroboscopic imaging, high speed image analysis, and EM to analyze the control of the beat frequency, waveform and coordination of respiratory cilia. We have developed correlative LM/EM methods and correlative live/immunofluorescence methods for this purpose. These studies have import for 1) detecting and understanding abnormal parameters of ciliary function, as in primary ciliary diskinesis (PCD) 2) for the testing of exogenous agents (drugs, environmental agents, etc.) on mucociliary transport. 2) Along with 4 other UB labs in Chemistry and Engineering, plus 1 lab in Head and Neck Surgery Dept. at Roswell Park, our lab is involved in an interdisciplinary project to develop a “high tech bandage” that is doped with tissue specific growth factors and cytokines that can be released with full activity and at known rates to stimulate wound healing in scrape and burn types of acute (and potentially, chronic) injuries. These agents are selected to promote: a) the motogenic and mitogenic activity of epithelia and b) blood vessel formation. Our lab specifically is responsible for the in-vitro testing of doped membranes for their ability to promote wound closure (re-epithelialization of 9 mm wounds) in a human epidermal cell line by image analysis of wound closure kinetics and cell division and cell death rates. We also are responsible for the in-vivo testing of such membranes in animals using a porcine burn model to assay inflammation, epithelial closure rates, blood vessel formation, and inflammation. As a faculty member and Co-Director of one of the oldest biological imaging courses in the U.S. (Optical Microscopy and Imaging in the Biomedical Sciences Course, Marine Biology Laboratory, Woods Hole, MA) my lab frequently is asked to help other researchers with digital imaging problems and has contributed computerized digital image analyses in a number of scientific publications.
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.
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.
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.
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 nutrient iron. Since in eukaryotes, iron metabolism depends on the activity of copper-containing enzymes called ferroxidases, we examine the trafficking copper in cells as well. The first challenge for a cell is to scavenge these two metals from the environment. This is true for a yeast cell in culture, or for an epithelial cell in your intestine. 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 both are toxic. Iron and copper are essential micronutrients. 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 to support the elevated energy metabolism needed to support neuronal function. However, both iron and copper are also intrinsically toxic. This toxicity 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.
Toxicology and Xenobiotics
Dr. Paul Kostyniak‘s primary research program has focused on the toxicology of heavy metals, chlorinated organics, and antidote development. His lab is studying mechanisms of xenobiotic disposition and investigating the role of exogenous nutrients in the elimination of toxic pollutants. Other ongoing projects involve the assessment of risk associated with exposure to PCB isomers found in fresh water fish; and the development and testing of antimicrobial surface coatings. As the director of the Toxicology Research Center, Dr. Kostyniak has organized an interdisciplinary research and teaching program which applies the expertise of toxicologists, pharmacologists, chemists, acquatic biologists, biochemists, pathologists, epidemiologists, geologists and physicians to basic and applied research problems in toxicology. The Center conducts coordinated scientific inquiries into health problems created by toxic chemicals. Dr. Kostyniak also oversees the center‘s analytical toxicology laboratory and the center‘s Atlantic OSHA Professional Education Program.
Apoptosis and cell death; Endocrinology; Molecular and Cellular Biology; Gene Expression; Regulation of metabolism; Signal Transduction
Suzanne Laychock, PhD, is senior associate dean for faculty affairs and facilities, and professor of pharmacology and toxicology. She is responsible for overseeing faculty development, space management, and undergraduate biomedical education programs. Dr. Laychock earned a bachelor’s degree in biology from Brooklyn College, a master’s degree in biology for the City University of New York and a doctorate in pharmacology from the Medical College of Virginia. An accomplished scientist, Dr. Laychock’s research focuses on endocrine pharmacology with an emphasis on signal transduction mechanisms involved in insulin secretion and models of diabetes mellitus. The author of numerous journal articles, she has served as associate editor of the research journal LIPIDS, and on the editorial boards of Diabetes and the Journal of Pharmacology and Experimental Therapeutics. She is the recipient of research grants from, among others, the Juvenile Diabetes Research Foundation, the National Institutes of Health, and the American Diabetes Association. Dr. Laychock is Council Member and has chaired the Women in Pharmacology Committee of the American Society for Pharmacology and Experimental Therapeutics. She has served the university as a member and chair of the President’s Review Board, and as co-director of the Institute for Research and Education on Women and Gender.
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. My research has found that drugs acting on imidazoline I2 receptors may produce analgesic effects that are devoid of opioid-like side effects. I am continuing this line of research to further delineate the pharmacological properties of these drugs--how they work, how effective and safe they are, and how long the beneficial effects last--as a novel class of analgesics. Second, I am interested in pharmacotherapy of stimulant abuse. Stimulants represent a large family of abused drugs, including traditional drugs of abuse such as cocaine and methamphetamine (“meth”) and valuable pharmacotherapies such as Adderall and Ritalin. Stimulant abuse and addiction remain challenging problems that lack FDA-approved pharmacotherapies. 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 pharmacotherapeutic treatments. One unifying theme of the ongoing research in my laboratory is the application of receptor theory to the guidance and interpretation of the drug interactions in behaving animals. The long-term goal of my laboratory is to develop new analgesics for pain control and pharmacotherapeutics for stimulant addiction.
Bioinformatics; Gene Expression; Genomics and proteomics
My research is focused on developing bioinformatics algorithms especially through sequencing analysis and data integration, to understand better transcriptional and epigenetic regulation. Transcription factor often binds to DNA and interferes with transcription machinery to enhance or repress gene expression. Epigenetic features such as histone modification, chromatin remodeling factor binding, DNA methylation, and chromatin 3D organization add yet another layer of information, making it more complex to understand the regulation dynamics within the nucleus. With advancing sequencing technology, however, such information now can be measured and quantified in genome scale, though the growing number of big genomic datasets creates challenges as well as opportunities for bioinformatics methodologies. The focus of our lab is to build algorithms, analysis platforms and databases to integrate big datasets from the public domain into various biological questions and disease models. The MACS (Genome Biology 2008) algorithm, on which I worked to develop, is one of the most widely-used algorithms for predicting cis-regulatory elements from Chromatin Immunoprecipitation with high-throughput sequencing (ChIP-seq). The algorithm has been evolving over years to accommodate various factor types from punctuate transcription factor binding to long-range histone modifications. It has been used to process hundreds of publicly-available datasets in the mod/ENCODE project, and it continues as a focus of my lab. I also worked to build an integrative platform for ChIP analysis based on Galaxy framework, named Cistrome (Genome Biology 2011). This platform provides both a user-friendly interface and rich functionality for biologists to manage and process their high-throughput genomic data and to publish the results conveniently over the Internet. The Cistrome platform will continue as a collaborative project between my UB lab and research partners at Harvard University. I have also been involved in many collaborative research projects, such as circadian binding of histone deacetylase and nuclear receptor Rev-Erba in mouse liver (Science 2011), and the modENCODE consortium project to elucidate chromatin factor functions of C. elegans (Genome Research 2011 and Science 2010).
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.
Function and Structure
Current interests: 1) Killing techniques (forensic pathology) of extant and extinct big cats and cat-like carnivores (sabertoothed forms), 2) virtual clinical training platforms, and 3) determining best practices for managing sprains and other soft tissue injuries.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Genomics and proteomics; Molecular genetics; Stem Cells; Transcription and Translation; Transgenic organisms; Vision science
My lab is interested in how global gene expression advances from one state to the next in time and space during development to promote the specification and differentiation of individual retinal cell types from multi-potent neural progenitor cells. We focus on the gene regulatory network (GRN) involved in the formation of one retinal cell type, retinal ganglion cells (RGCs). RGCs are the only projection neurons in the retina and connect the retina to the brain through the optic nerve. Death of RGCs is cause of vision loss in glaucoma and other retinal diseases. Several key transcription factors (TFs) functioning at different stages of RGC development have been identified; Math5 is essential for RGC fate specification, whereas Pou4f2 and Isl1 are required for their differentiation. Our previous study has established a tentative model for the RGC GRN, in which these TFs occupy key node positions. Current projects in the lab are aimed at further understanding how these transcription factors specifically regulate their target genes and how they interact with each other. Considerable efforts are also placed on identifying novel key regulators in the GRN. Our studies employ a combined approach of genetics, genomics and bioinformatics. Our eventual goal is to use the knowledge learned from our studies to develop new therapies for various retinal diseases.
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.
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.
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 close or intracellular and related bacteria that form an 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. One project involves understanding 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. We initiated a new project to understand the requirement for manganese in cellular processes, how it is acquired from the environment, and how manganese controls gene expression. Also, we identified cross-talk between regulators that control iron and manganese homeostasis and are pursuing this unique mechanism.
Toxicology and Xenobiotics
Assessing the Health Risks of Exposures to Organophosphate (OP) Pesticides • Characterization of the in vitro and in vivo metabolism and disposition of OP pesticides in animal models and humans. • Identify new biomarkers of susceptibility to OPs by investigating the function of genetic variants in key enzymes (CYP2B6, CYP2C19, PON1) which regulate OP metabolic activation and detoxification. • Investigate the relationship between biomarkers of exposure, effect and susceptibility in human populations with environmental and occupational exposures to pesticides. • Utilize enzyme-specific physiologically based pharmacokinetic /pharmacodynamic (PBPK/PD) models to better assess human exposure, target tissue dose and subsequent effects of OPs. Assessing the Biological and Toxicological Effects of Exposures to Persistent Halogenated Aromatic Hydrocarbons, Including Dioxins, Polybrominated Diphenyl Ethers (PBDEs) and Polychlorinated Biphenyls (PCBs). • Assessing Human Exposures to dioxins, PBDEs, and PCBs • Characterize the metabolism and disposition of dioxins, PBDEs, and PCBs in humans. • Utilize toxicogenomic approaches to understand the relationship between exposures to dioxins and/or PCBs that are ligands for the Ah receptor and mechanisms for their adverse health effects.
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.
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 HCO3- 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.
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.
Gene Expression; Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; Transcription and Translation
Our laboratory utilizes combined genetic, biochemical and molecular biological approaches to investigate the molecular mechanisms involved in the initiation and regulation of eukaryotic transcription. Previous work in our laboratory utilizing both the budding yeast Saccharomyces cerevisiae and human cells resulted in the identification and biochemical characterization of mutants of nuclear RNA polymerase II (RNAPII) and the general transcription factors TFIIB and TFIIF that coordinately affect transcription start site utilization and transcript elongation. These studies supported a model where yeast and human TFIIF induce global conformational changes in RNAPII that result in structural and functional changes in the polymerase active center. Our current studies are focused on elucidating the mechanisms of kinetoplast transcription by the mitochondrial RNA polymerase of Trypanosoma brucei. T. brucei is a protozoan parasite that is the causative agent of African sleeping sickness (trypanosomiasis) in humans and nagana in animals. Procyclic trypanosomes growing in the midgut of the tsetse fly have a fully functional mitochondrion whereas trypanosomes in the mammalian bloodstream exhibit repressed mitochondrial function. The mitochondrial DNA in trypanosomes is unusual in its structure, comprising a highly catenated network of maxicircles and minicircles termed kinetoplast DNA (kDNA). Surprisingly, very little is known about the cis-acting elements and the trans-acting factors governing the transcription of maxicircles and minicircles. Our objective is to elucidate the mechanisms and regulation of T. brucei kDNA transcription with the ultimate goal of developing therapeutic agents.
Neurodegenerative disorders; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Signal Transduction; Protein Function and Structure; Neuropharmacology
I focus my research on 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.
Bioinformatics; Genomics and proteomics; Signal Transduction; Toxicology and Xenobiotics
Our laboratory seeks to understand hormone-triggered nuclear receptor signaling. Nuclear receptors are associated with various diseases including diabetes and cancer and the availability of several high resolution structures of their ligand binding domains make them attractive targets for drug discovery. Eight of the top 100 prescription drugs (accounting for about US $9 billion in sales) target a nuclear receptor. However, these drugs can cause a variety of side effects and some patients develop drug resistance. Tamoxifen, a drug designed to selectively target the nuclear estrogen receptor which is present in 70% of breast cancer patients, induces substantial regression of breast tumors and an increase in disease-free survival. Tamoxifen binds directly to the ligand binding domain of estrogen receptor and regulates estrogen-mediated growth of breast cancer cells. Tamoxifen mimics estrogen effects in other tissues thereby providing some beneficial effects including reduced risk of osteoporosis. However, breast cancers that initially respond well to tamoxifen tend to develop resistance and resume growth despite the continued presence of the antagonist. We specifically focus on protein interactions that regulate estrogen signaling by binding to estrogen receptors. Our objective is to identify the estrogen receptor conformation-sensing regions of the interacting proteins and to discover potential small molecule sensors using state-of-the art bioinformatics and structure-based discovery tools and use them to generate a new breed of small molecular therapeutics for breast cancer therapy.
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.
My research for the last 25 years has focused on carbohydrate antigens that are important in cancer and in infectious disease (bacterial, viruses and parasites). These structures play important roles in the growth, adhesion and spread of cancer cells and bacteria and viruses. Immune responses to these structures can therefore be an effective mechanism to decrease disease. The anti-carbohydrate immune response is usually T cell independent, more difficult to develop and less in magnitude than the immune response to proteins.My long-term goals involve using information obtained about carbohydrates of related structures to manipulate the anti-carbohydrate immune response to improve clinical outcome. This work has involved use of synthetic oligosaccharides conjugated to bovine serum albumin as antigens, the use of structurally related synthetic oligosaccharides in inhibition studies, the use of antibody to carbohydrates in immunotherapy and immunolocalization of cancer, the use of genetic analysis of genes related to carbohydrate synthesis and adhesion, bacterial vaccine stability assays and bacteria rapid diagnosis assay development. The immunochemical aspects of this work were performed to determine the immunodominant regions of the sugars and the effects of small structural changes in the inhibitory oligosaccharides on the immunologic reaction. I have been involved in research concerning the immune response to carbohydrate antigens since 1984, through experience gained while a post-doctoral fellow at Roswell Park Cancer Institute (RPCI), gaining clinical diagnostic experience with Dr. T. Ming Chu, (the discoverer of Prostate Specific Antigen for diagnosis) and then carbohydrate experience with Dr. Khushi Matta (Carbohydrate synthetic chemist). Since that time, I have been involved in the development of monoclonal and polyclonal antibodies to defined saccharides as diagnostic markers or as vaccine candidates in both bacterial and cancer research. My laboratory, RPCI based for the first 9 years, and now at UB for the last 13 years, has had an emphasis on tumor associated carbohydrate antigens, and recently has been involved in 2 patent applications, “Use of anti-TF antibody to block metastasis of TF- antigen bearing tumors” (K R Olson, principle inventor of JAA-F11 monoclonal antibody), and “Carbohydrate Antigen-Nanoparticle Conjugates and Methods for Inhibiting Metastasis in Cancer” (K R Olson, co-inventor). Thomsen-Friedenreich antigen (TF-Ag) is a tumor associated antigen that is exposed in many types of carcinoma cells including breast, prostate, colon, and bladder.
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.
Neurodegenerative disorders; Apoptosis and cell death; Membrane Transport (Ion Transport); Proteins and metalloenzymes; Signal Transduction; Toxicology and Xenobiotics
Dr. Jerome Roth‘s research interests over the past several years have focused on the mechanism of action of manganese in producing neuronal cell death. Manganese is an essential mineral that at high concentration acts as a neurotoxin which produces a Parkinson-like syndrome. Although the identified brain lesions associated with manganism differ from those of Parkinson’s disease, there is increasing evidence that chronic exposure to Mn correlates with increased susceptibility to develop Parkinsonism. Current studies are focused on characterizing the signal transduction pathways stimulated by manganese and to determine whether they also play a role in the toxic actions of this divalent cation. As part of this project we are also investigating the transport mechanisms by which manganese is taken up into cells. We have focused our studies on the divalent metal transporter (DMT1) and its role in the transport of manganese and other divalent cations. We are currently studying the transcriptional and post-translational factors that regulate its expression in vivo. Preliminary studies have linked DMT1 expression to the protein, parkin, mutations in which lead to early onset of Parkinson‘s disease. Whether other gene linked to Parkinsonism are also associate with development of manganism is the current focus of my research. Current studies in my laboratory focus on how other early and late genes associated with Parkinson’s disease can influence Mn toxicity as these studies will provide a basis for the comorbidity between manganism and Parkinson’s; the manipulation of this mechanism may therefore provide new prophylactic and/or management treatment options for Parkinson’s disease.
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 Diseases; 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.
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 and building novel biomedical instruments, e.g., handheld devices that will allow noninvasive microscopic and tomographic optical imaging. This work will build on my previous research and expand into translational research that will directly support human health. My laboratory’s broad goal is to decipher meaningful information from anatomical structures and their pathologic conditions and connect them with molecular information to gain a better understanding of biological processes and disease. We focus on developing novel quantitative image processing and analysis methods, incorporating physical as well as statistical information of biological structures and their associated functional genomic information. Using statistical analysis, we have shown that our methods perform significantly better than existing ones. Existing methods in biomedicine typically do not employ both physical and statistical parameters associated with the imaging object and imaging system--and their environmental factors--while analyzing data. Thus, the results are often error-prone. By uniquely utilizing concrete physical and statistical modeling of the measurement data, our goal is to provide a more realistic profile and interpretation of complex biological systems and diseases. This, in turn, will provide new insights into diseases and improve disease diagnosis. My 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 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.
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.
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) regulation of transmitter release by metabotropic receptors 2) properties of glycine receptors in retina and in expression systems; 3) glutamate receptor function in development and neuronal cell death; 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.
Structural Biology; X-ray Crystallography; Bioinformatics; Proteins and metalloenzymes; Protein Function and Structure
Dr. Edward Snell is a Senior Scientist and Cheif Executive officer at the Hauptman-Woodward Medical Research Institute and faculty at the SUNY University at Buffalo Department of Structural Biology. He is a board member on the International Organization for Biological Crystallization, a member of the MacCHESS (The Macromolecular diffraction facility at Cornell High Energy Synchrotron Source) Advisory Committee and a member of the executive committee for the Stanford Synchrotron Radiation Lightsource users organization. He serves as a reviewer for multiple international Journals and both national and international funding agencies. He is on the American Crystallographic Association Communications Committee and chair-elect of the Biological Macromolecules Scientific Interest Group. His research group uses complementary techniques to extract structural and dynamic information from biological macromolecules. This research includes the development of crystallization methodology and the resulting analysis with an emphasis on high-energy light sources. Other techniques in use include Electron Paramagnetic Resonance and spectroscopy. He is experienced in solution scattering techniques, having organized and taught at both national and international meetings. The Snell laboratory research is supported by NIH, NSF, DoD, and NASA in addition to non-federal sources.
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.
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.
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.
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.
My research is aimed at determining how nerve cells establish appropriate connections during the development of the nervous system. 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 recently begun to clarify the fact that glutamate receptors are integral to this process. 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 systems. 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.
Structural Biology; X-ray Crystallography; Bioinformatics; Genomics and proteomics; Infectious Disease; Microbial Pathogenesis; Molecular and Cellular Biology; Protein Function and Structure; Proteins and metalloenzymes; Virology
The overarching goal of the Umland Lab is to use structural biology combined with biochemical, molecular biology, and genetics to explore important elements of infectious disease. The objective is to both extend the fundamental understanding of how microbial pathogens interact with their respective hosts and to identify new antimicrobial targets and new antimicrobial therapeutics. Two major projects on this theme are on going within the lab. In the first, unrecognized and underexploited potential antimicrobial targets within multi-, extreme, and pan-drug resistant gram-negative bacilli (GNB) are being identified and then characterized using the phenotype of in vivo essentiality. That is, our interest is in genes and their corresponding gene products that are essential for bacterial growth and survival during infection of a host (i.e., in vivo) rather than only essential under ideal laboratory growth conditions (e.g., rich laboratory media, absence of immune responses, etc.). The class of genes that are in vivo essential but not in vitro essential has largely been neglected as antimicrobial targets, and so represents a rich set for expanding target space in the urgent race to develop new antimicrobials. The second project is focused upon identifying and characterizing virus protein - host protein interactions. Viruses encode a highly limited set of functionality, and therefore rely on subverting cellular machinery. This high jacking of cellular functions for the benefit of the virus often involved virus-host protein-protein interactions (PPIs). Study of these virus-host PPIs reveals both the mechanisms by which viruses co-opt cellular functions and potential new antiviral targets recalcitrant to the development of drug resistance. An additional rationale for studying virus-host PPIs is to understand virus evolution with respect to PPI involvement in virulence, pathogenesis, and host tropism. In conjunction with both of these projects, the Umland Lab is using structurally enabled fragment-based lead discovery (FBLD) methods to identify small molecules with potential to be developed into antimicrobial therapeutics.
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. Additionally, I lecture in Microbiology for Undergraduates.
Cell growth, differentiation and development; Microbiology; Molecular Basis of Disease; Molecular and Cellular Biology; Regulation of metabolism; Signal Transduction; Toxicology and Xenobiotics; Vitamins and Trace Nutrient
Dr. Willsky’s research focuses on the role of oxovanadium compounds in cellular metabolism. V is a trace metal believed to be required for growth. Oral administration of oxovanadium compounds alleviates the symptoms of Diabetes in animal models and humans. The techniques of genetics, microbiology, molecular biology, biochemistry, pharmacology, magnetic resonance spectroscopy, and cell physiology are used. The diabetes-altered gene expression of genes involved in lipid metabolism, oxidative stress and signal transduction is returned to normal by V treatment of rats with STZ-induced diabetes, as demonstrated using DNA microarrays. Inhibition of tyrosine protein phosphatases is believed to be a major cause of the insulin-like effects of V. Our results implicate the interaction of V with cellular oxidation-reduction reactions as being important in the anti-diabetic mechanism of V complexes. A new project in the lab studies the mode of action of medicinal plant mixtures used by the native healers of Peru.
Behavioral pharmacology; Neuropharmacology; Toxicology and Xenobiotics
Research in my laboratory centers on the study of psychoactive drugs with special emphasis on nootropics and drugs of abuse. In collaboration with Dr. Richard Rabin of this department, behavioral data are correlated with biochemical indices of drug action in an attempt to understand at the receptor level the effects in intact animals of psychoactive drugs. Behavioral data are obtained using the techniques of operant behavior with special emphasis on the phenomenon of drug-induced stimulus control. Current interests include the serotonergic basis for the actions of indoleamine and phenethylamine hallucinogens including LSD and [-]-DOM as well as their interactions with selective monoamine reuptake inhibitors such as fluoxetine [Prozac]. In the area of nootropics, recent studies have examined the effects of EGb 761, an extract of Ginkgo biloba; for these investigations, a delayed non-matching to position task in a radial maze is employed. Currently, studies are in progress to assess the serotonergic basis for the cognitive effects of drugs of abuse including LSD and MDMA [Ecstasy]. Behavioral pharmacology of psychoactive drugs, including psychotherapeutic agents and drugs of abuse; mechanisms of action of hallucinogens. Research in Dr. Jerrold Winter‘s laboratory seeks to understand the ways in which drugs alter behavior. Many chemicals are candidates for study but attention in the last few years has centered on hallucinogens such as LSD, phencyclidine, DOM, and ibogaine. Another area of major interest is age-related memory impairment and those natural materials, including ginseng and gingko biloba, which are purported to influence that impairment. The behavioral effects of these drugs are studied in rats trained with the techniques of operant conditioning. Specific variables in use at the present time include drug-induced stimulus control, radial maze acquisition and performance, and conditioned place preference and aversion. In addition, Dr. Winter actively collaborates with Dr. Richard Rabin of the Department of Pharmacology and Toxicology in order to correlate behavioral effects with biochemical indices of action at the receptor level and with functional efficacies in second messenger systems.
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.
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.
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.
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.