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This directory lists MSTP faculty from the 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 Summary:
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
Research Summary:
I have over 25 years of experience with the design, development and use of immunodeficient mouse human tumor xenograft models to study the interaction of inflammatory leukocytes and fibroblasts with tumor cells in human lung and ovarian tumor microenvironments. My co-investigators and I have established that tumor-associated T cells are hypo-responsive to activation via the T cell receptor (TCR). We determined that the failure of these cells to respond to activation signals is due to the disruption of the TCR signaling cascade that occurs at or just proximal to the activation of PLC-γ. We have found that an identical TCR signaling arrest occurs in human T cells present within chronic inflammatory tissues. Using human tumor xenograft models my students and postdoctoral fellows 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 that mobilizes an immune mediated eradication of the tumor. Based upon these preclinical studies we have begun a Phase I clinical trial to test the safety and feasibility of delivering low and sustained doses of recombinant human IL-12 directly into patients’ tumors. Most recently we have determined that lipids present within human ovarian tumor ascites fluids mediate a reversible arrest in the TCR signaling pathway of ovarian tumor-associated T cells. A major focus of my laboratory is to structurally identify the immunoinhibitory factors present within the tumor ascites fluids, determine the mechanism by which they arrest the TCR signaling, and using a novel humanized mouse model to preclinically test whether the TCR signaling arrest can be reversed in tumor-associated T cells or prevented from occurring in T cells upon entry into the tumor microenvironment by eliminating or blocking the lipid mediated disruption of the TCR signaling cascade.
Specialty/Research Focus:
Drug abuse; Circadian Rhythm/Chronobiology; Gene Expression; Molecular and Cellular Biology; Neuropharmacology
Research Summary:
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.
Specialty/Research Focus:
Genomics and proteomics; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Protein Function and Structure; Proteins and metalloenzymes
Research Summary:
Research in my laboratory is directed at understanding basic questions concerning structure-function relationships in ion channels. We are especially interested in using a variety of naturally-occurring toxins as probes of both ion transport and gating processes in these transmembrane macromolecules. To better understand the nature of these toxin binding sites, we have cloned and expressed synthetic genes which encode polypeptide modulators of voltage-sensitive sodium and calcium channels and also of a peptidic blocker of the gastric-chloride channel. By creating designed mutant forms of these toxins, and characterizing their functional properties and 3-dimensional structures, we hope to construct a picture of the channel region involved in binding. Complementary mutagenesis of channel products helps to define the structure of the channel itself, and this information is not accessible via other experimental approaches. Definition of toxin regions essential for this interaction will also allow us to design useful pharmacological agents directed at the target channel.
Specialty/Research Focus:
Bioinformatics; Genomics and proteomics; Molecular and Cellular Biology; Molecular genetics; Gene Expression; Transcription and Translation
Research Summary:
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.
Research Summary:
Our research interests focus on microbial pathogenesis, particularly on the identification and characterization of bacterial virulence factors and putative vaccine antigens for the gram-negative human pathogens: Moraxella catarrhalis and Acinetobacter baumannii.
I. One major area of focus involves the gram-negative human pathogen Moraxella catarrhalis. This bacterium predominantly causes middle ear infections and sinusitis in infants and children, and lower respiratory tract infections in adults. This organism is the third leading cause of otitis media and it is estimated that approximately 50% of children will become colonized by this bacterium in the first six months of life.
M. catarrhalis-related projects ongoing in the lab:
A. One prominent bacterial surface component implicated as a potential virulence factor is the lipooligosaccharide (LOS) molecule. Structural studies show that M. catarrhalis LOS is similar to the LOS of other Gram-negative human mucosal pathogens. Currently there is interest in defining the role of LOS in pathogenesis and in determining the assembly and expression of this major surface glycolipid. The focus of this work is to perform a comprehensive analysis of the genetics and biology of M. catarrhalis LOS.
B. We have now demonstrated that M. catarrhalis express peritrichious type-IV pili. Our studies indicate pilus production by this bacterium is essential for DNA uptake by natural transformation and undergoes iron-responsive regulation. Additional studies will focus on elucidating the prevalence and role of type IV pili in the pathogenesis and host response of M. catarrhalis infections. We have also entered into a collaborative study using a Chinchilla colonization model in order to correlate our in vitro studies with a relevant in vivo biologic system.
C. In addition, we are also attempting to identify specific bacterial factors involved in attachment to host tissues. M. catarrhalis often colonizes the mucosal surfaces in the nasopharynx of young children. There is a strong correlation between colonization and subsequent development of otitis media. We have recently identified a two-partner secretion (TPS) locus in M. catarrhalis termed MCH (M. catarrhalis hemagglutinin-like proteins). The MCH locus consists of three open reading frames: mchA1 and mchA2 encode homologues to the filamentous hemagglutinin of Bordetella pertussis, mchB encodes the TPS transporter. We are currently characterizing this region and are investigating the function of the M. catarrhalis TPS locus.
II. Acinetobacter baumannii, a Gram-negative pathogen, causes nosocomial infections in susceptible populations. This organism has the ability to persist for extended periods on abiotic surfaces suggesting that these bacteria form biofilms. Recently, the military has seen an increased prevalence of multi-drug resistant Acinetobacter-infections in wounded soldiers returning from Iraq and Afghanistan increasing interest in studying this under-characterized pathogen.
A. baumannii-related projects ongoing in the lab:
A. The biosynthesis and expression of the lipopolysaccharide (LPS) molecule of A. baumannii is a new research focus of our laboratory. LPS is a common constituent of the outer membrane of Gram-negative bacteria and studies are underway to define the role of LPS in the pathogenesis in A. baumannii infections. Studies of defined mutants that can no longer express full-length LPS molecules will yield important insights into the virulence of this opportunistic pathogen.
B. Nosocomial A. baumannii infections have been linked to the fact that A. baumannii colonizes hospital equipment and the organism is able to resist physical and chemical disinfection by forming biofilms. One of the bacterial factors that have been shown to play a role in abiotic surface attachment, persistence and virulence is the polysaccharide poly-N-acetylated glucosamine (PGA), a large extracellular polysaccharide. We have identified a PGA-encoding locus in A. baumannii that shares homology with the previously described pga locus of E. coli, A. pleuropneumoniae, and A. actinomycetemcomitans and the homologous PNAG/PIA-encoding ica locus in S. aureus and S. epidermidis. We are interested in investigating the functional role of the PGA expressed by A. baumannii.
C. We have identified an approximately 26-kb open reading frame in the A. baumannii chromosome that encodes a large outer membrane protein homologous the biofilm-associated protein (Bap) of Staphylococcus aureus. We have produced monoclonal and polyclonal antibodies to the A. baumannii Bap-homologue and generated a transposon mutant defective in Bap expression. Our analyses indicate this protein is expressed on the bacterial surface and is conserved among clinical isolates. Additional studies will focus on the contribution of this molecule to biofilm formation and adherence of A. baumannii to abiotic surfaces.
Specialty/Research Focus:
Cardiology; Cardiovascular Disease
Research Summary:
As Chief of the Division of Cardiovascular Medicine, I am responsible for overseeing the clinical, teaching and research programs of the Division of Cardiology at the University at Buffalo. I see outpatients in our ambulatory cardiology practice as well as attend in the CCU at the Buffalo General Hospital and Department of Veterans Affairs Medical Center. We are currently transitioning all of the cardiovascular programs to the new Global Heart and Vascular Hospital adjacent to the Buffalo General Hospital. On top of this new facility will be the UB Clinical and Translational Research Center which will house laboratories, a clinical research center and a new translational cardiovascular imaging facility. We look forward to occupancy of this innovative, state-of-the art facility in early 2012.
In terms of scientific investigation, our group has a longstanding interest in understanding the adaptive and maladaptive responses of the heart to chronic repetitive ischemia. We conduct translational research in preclinical models of ischemic heart disease and pursue parallel patient oriented investigation in humans with chronic coronary artery disease. Basic investigation involves three major areas which are all directly relevant to human cardiovascular disease and are summarized below.
The first area focuses on identifying the intrinsic adaptive responses of the heart that arise from repetitive ischemia or angina and result in viable, chronically dysfunctional or “hibernating myocardium”. This is an important pathophysiological state to identify clinically since in contrast to a heart attack where the muscle is scarred, left ventricular dysfunction is at least partially reversible with revascularization. To accomplish investigation with this problem, we use high throughput proteomic approaches employing 2D-differential in gel electrophoresis and mass spectrometry as well as transcriptional profiling with gene arrays (in collaboration with colleagues at the New York State Center of Bioinformatics and Life Sciences). We have identified that myocyte cellular remodeling, rather than fibrosis, accounts for the persistent dysfunction frequently observed after coronary revascularization. With this information, we can identify new molecular targets for therapeutic intervention.
The second area of investigation involves studies centered on understanding the mechanisms responsible for effecting intrinsic cardiac repair with resident adult stem cell populations residing in the bone marrow and heart. We have demonstrated that a number of diverse interventions (e.g. adenoviral overexpression of FGF-5, selected cholesterol lowering medication such as pravastatin and intracoronary mesenchymal stem cells) all improve myocardial function yet have no effect on myocardial blood flow. The functional improvement appears to arise from endogenous myocyte proliferation which, with each intervention, is accompanied by mobilization of cKit+ and CD133+ bone marrow progenitor cells to the heart. These interventions all stimulate cardiac myocytes to reenter the cell cycle and replace myocytes that were lost via apoptosis during repetitive ischemia. They afford a great potential to effect cardiac repair in pathophysiological states that are not due to irreversible fibrosis. This work is highly relevant to advancing therapeutic options available for patients with heart failure.
The third area of study centers on understanding how chronic ischemia and cellular remodeling predisposes to the development of sudden cardiac arrest form ventricular fibrillation. We have demonstrated considerable spatial inhomogeneity in function, perfusion, cellular and molecular remodeling in hibernating myocardium that results in a substrate that develops spontaneous ventricular fibrillation in the absence of overt evidence of acute ischemia or infarction. We can identify this substrate in vivo by using molecular imaging of myocardial sympathetic innervation with positron emission tomography (PET) and 11C-meta-hydroxyephedrine (HED) which is severely reduced in hibernating myocardium. We are currently pursuing investigation to determine whether continuous telemetry or circulating biomarkers can also be used to predict the remodeling that leads to an increased susceptibility to sudden cardiac arrest from ventricular fibrillation. Our long-term goal is to identify whether there are substrate markers that can better predict the likelihood that spontaneous arrhythmias develop prior to cardiac arrest. This is important since approximately one in three patients present with sudden death in the absence of a heart attack as their first and only manifestation of heart disease.
Finally, we are actively involved in extending our findings in the laboratory to the care of patients with heart disease. As an example, we have translated our preclinical observations to humans through an NIH sponsored clinical trial intended to determine whether imaging myocardial scar or reduced norepinephrine uptake in viable, dysfunctional myocardium with HED and PET can identify a substrate predictive of an increased risk of sudden cardiac death in patients with chronic left ventricular dysfunction. The PAREPET study (Prediction of Arrhythmic Events with Positron Emission Tomography) will determine whether PET imaging can be used to risk stratify patients for sudden death who will be the most likely to benefit from implantation of an implantable cardiac defibrillator (ICD). If successful, this approach could help identify a patient population with relatively preserved left ventricular function who would benefit from the primary prevention of sudden cardiac death by placement of an implantable cardiac defibrillator. While the rate of sudden death events is lower in this group, they account for a large number of events.
Our academic environment provides a rich opportunity for training in translational cardiovascular medicine. Our long-term goal is to advance the care of patients with heart disease through clinical practice and scientific investigation. Through scientific advances, we hope to contribute to preventing the progression of heart failure and preventing the development of sudden cardiac death.
Specialty/Research Focus:
Molecular and Cellular Biology; Neurobiology; Neuropharmacology
Research Summary:
The core of my current research is ‘systems pharmacology‘, in which I am elucidating the biological function of the novel neuropeptide urotensin II (UII). The characterization of novel neuropeptide systems has been the topic of both my graduate studies (urotensin II; Clark et al., 2001, 2005; Huitron-Resendiz et al., 2005) and my second post-doctoral fellowship (neuropeptide S; Xu et al., 2004; Jüngling et al., 2008; Duangdao et al., 2009; Okamura et al., 2011; Clark et al., 2011). My ultimate research goal is to elucidate the endogenous function of the novel neuropeptide urotensin II. With my existing R00 grant from NIDA, I will establish whether activation of the UII receptor (UIIR) modulates reward behaviors.
In addition, I am currently investigating the nuances of urotensin II receptor signaling and the effects of naturally occurring variants within the coding regions. In these investigations I am furthering my expertise from training I received during my post-doctoral fellowships (Van Craenenbroeck et al., 2005; Clark et al., 2010; Gill et al., 2010). I believe that the parallel investigation of the receptor pharmacology and behavioral pharmacology will expedite the unraveling of the role of the UII system in human biology.
Specialty/Research Focus:
Allergy and Immunology; Infectious Disease; Medical Microbiology; Microbiology; Genomics and proteomics; Immunology; Microbial Pathogenesis; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Gene Expression; Signal Transduction
Research Summary:
My laboratory researches complementary aspects of host-pathogen interactions through two distinct projects in the fields of immunology and bacterial pathogenesis.
In the field of immunology, we study the cellular and molecular mechanisms that regulate mucosal immune responses by stimulating the immune system with enterotoxins produced by certain strains of E. coli. Mucosal immune responses provide critical protection against microbial pathogens that invade through the body’s mucosal surfaces (the gut, the oral cavity, the urogenital system, and the respiratory system). The enterotoxins we employ are potent mucosal adjuvants which enhance mucosal and systemic immune responses to foreign antigens when administered concurrently. In addition to describing these immune regulation mechanisms that respond to the enterotoxins, our research can also support the development of new mucosal vaccines.
In the field of bacterial pathogensis, our research analyzes the genetic factors in four pathogenic species of the Bordetellae that enable these microorganisms to scavenge iron from host tissues. The ability of these bacterial pathogens to infect a host depends upon the bacteria acquiring iron from that host using receptors and accessory proteins encoded by specific gene clusters, including hurIR-bhuRSTUV and ecfIR-bfrH. Extracellular signals control expression of these gene clusters by regulating specific sigma factors (ECF). Information obtained in these experiments will provide the means to create drugs to abrogate acquisition of iron, an essential nutrient, and identification of new antigens that can be employed as vaccine targets.
Specialty/Research Focus:
Endocrinology, Diabetes and Metabolism
Research Summary:
Vascular cell reactivity encompassing platelet function, endothelial function, monocyte/macrophage function and the interactions between them (adhesion molecules viz lCAM, VCAM, P-selectin, L-selectin, E-selectin, etc.). Reactive Oxygen Species (ROS) in diabetes, atherosclerosis, hypertension, aging, infection, etc. and a consequential damage to
lipids, proteins and DNA. Regulation of aromatase, the effect of estrogen on estrogen receptor, androgen receptor and glucocortico receptor (elucidationi of pre- and post-receptor mechanisms in menopause, etc.). Venous reactivity with measurements of venous diameter and flow velocity and the effect of various drugs in NIDDM, IDDM, and IGT. Genetic regulation of aromatase and estrogen receptor. The role of nitric oxide in vascular reactivity, vis-a-vis various complications of diabetes and other factors involved with vascular reactivity. Effects of endotoxin on adhesion molecules, PAF, platelets, ROS and procalcitonin.
Specialty/Research Focus:
Behavioral pharmacology; Cytoskeleton and cell motility; Gene Expression; Gene therapy; Neurobiology; Neuropharmacology
Research Summary:
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”. Indeed, there is great variability in individual rates of propensities toward relapse following cocaine use., We are looking at how molecular and behavioral plasticity mediates individual differences in susceptibility to drug abuse and relapse.
Specialty/Research Focus:
Drug abuse; Behavioral pharmacology; Signal Transduction; Neuropharmacology; Circadian Rhythm/Chronobiology
Research Summary:
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.
Specialty/Research Focus:
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
Research Summary:
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.
Specialty/Research Focus:
Apoptosis and cell death; Inherited Metabolic Disorders; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Regulation of metabolism; Transgenic organisms; Vision science
Research Summary:
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.
Specialty/Research Focus:
Autoimmunity; Cell growth, differentiation and development; Gene Expression; Immunology; Molecular and Cellular Biology; Molecular genetics; Signal Transduction; Transcription and Translation; Transgenic organisms
Specialty/Research Focus:
Ocular Pathology; Ophthalmology; Immunopathology; Protein Folding
Research Summary:
Work in my laboratory is aimed at uncovering basic mechanisms important to retinal function, and the application of molecular and cellular approaches to understanding the pathogenesis of ocular disease. My main long-term goal is to elucidate the mechanisms of photoreceptor / retinal pigment epithelium (RPE) interactions. A unique extracellular material known as the interphotoreceptor matrix appears to play a key role in these interactions. The main soluble protein component of this matrix is a high molecular weight glycolipoprotein termed interphotoreceptor retinoid-binding protein (IRBP). A long-term goal of my research is to understand the role of IRBP in vision.
Specialty/Research Focus:
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Genomics and proteomics; Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Neurobiology; Stem Cells; Transgenic organisms
Research Summary:
We are working on the Nuclear Factor I family of transcription factors. We are investigating their roles in development and analysis of their "regulomes", that is, all the genes regulated by the specific transcription factor. Our work focuses on loss-of-function mutations of the NFI genes in the mouse and C. elegans.
Specialty/Research Focus:
Apoptosis and cell death; Immunology; Infectious Disease; Membrane Transport (Ion Transport); Microbial Pathogenesis; Molecular and Cellular Biology; Regulation of metabolism
Research Summary:
My laboratory seeks to understand how the respiratory pathogen Streptococcus pneumoniae (pneumococcus), a gram-positive, extracellular bacterium, causes disease in humans and how human defense mechanisms, including breast milk, can better protect us from infection. Our team of undergraduate students, graduate students, a technician and a senior scientist work together and with several national and international collaborators to develop a better understanding in two areas.
First, we are interested in the protective effects of breast-feeding on bacterial infection. We have identified a protein-lipid complex in breast-milk, HAMLET (human alphalactalbumin made lethal to tumor cells) with strong bactericidal activity against S. pneumoniae and other respiratory tract pathogens. HAMLET‘s activity is especially important because it represents a new way to kill bacteria, even those resistant to antibiotics: it uses an essential pathway that the bacteria cannot become resistant against. Our current projects aim to understand the mechanism of HAMLET-induced bacterial death and the potential use of HAMLET or its targets in preventing and treating biofilm formation in vitro and established pneumococcal infections in vivo.
Second, we study how bacterial factors promote colonization and infection of the human host such as adherence, invasion, and biofilm formation, and how the host protects itself from bacterial challenge (mucosal innate and adaptive immune responses). We want to improve the understanding of how the pneumococci interact with host cells in the respiratory tract during colonization and transition to infection. We currently focus on dihydrolipoamide dehydrogenase (DLDH), a pneumococcal enzyme that the bacteria require to cause infection. We have shown that DLDH facilitates nutrient import by binding to a transport molecule only found in bacteria. Our current project aims to understand DLDH‘s function and target it for future development of novel antibiotics.
Specialty/Research Focus:
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Genomics and proteomics; Molecular genetics; Signal Transduction
Specialty/Research Focus:
Virology
Research Summary:
I consider myself a protein chemist, and I study the proteins on the surface of the HIV virus and how they get the virus into the cell—the initial step in HIV infection. My goal is to not only develop inhibitors to HIV entry, but also to translate it into something that is easy and economic to deliver. The HIV situation in undeveloped countries remains catastrophic, and I think it’s the responsibility of academic medical research to pursue solutions that a pharmaceutical company won’t because they’re not profitable. My approach is in improving upon protein therapeutics, finding novel ways to produce proteins in large abundance inexpensively.
Membrane proteins are a particular concentration of my research. I’m hoping that during my career there is going to be some key finding that helps us to better study membrane proteins. I’d love for it to happen in my lab.
Research Summary:
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, and the synthesis of the "elastic" material in blood vessels and and "connective" material in joint ligaments. However, these metals are also intrinsically toxic. This toxicity results from their strong tendency to generate oxygen radicals which in turn destroy key cellular components. The essentiality of these metals and their toxicity are illustrated by the diverse genetic disorders in copper and iron metabolism that result in a variety of human disease.
Specialty/Research Focus:
Apoptosis and cell death; Endocrinology; Molecular and Cellular Biology; Gene Expression; Regulation of metabolism; Signal Transduction
Research Summary:
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.
Specialty/Research Focus:
Cardiology
Research Summary:
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.
Specialty/Research Focus:
Cardiovascular Disease; Oncology; Pathophysiology; Regulation of metabolism; Signal Transduction
Research Summary:
My lab primarily seeks to understand the molecular mechanisms of coronary artery disease, the most common cause of age-related cardiovascular disease. I study the signaling mechanisms that underlie the reduced tolerance elderly patients’ hearts show to stress from restricted blood flow (ischemia) and the restoration of normal blood flow (reperfusion). My work aims to devise novel strategies to boost cardiac tolerance of these events in aged populations or prevent patients’ decline in resilience.
Closely tied to this work, my group explores the intrinsic relationship between diabetes and cardiovascular diseases. Evidence suggests that adenosine monophosphate-activated protein kinase (AMPK) may protect the heart from ischemic injury and limit the development of cardiac myocyte hypertrophy. This enzyme is activated by hormones, cytokines, and certain drugs used to treat type 2 diabetes. My lab is investigating AMPK’s role in regulating myocardial glucose metabolism. AMPK binds to adenosine monophosphate (AMP), through which it moderates enzymatic activity, balancing cellular production and consumption of adenosine triphosphate (ATP). We want to elucidate the molecular mechanisms responsible for AMPK activation, identify novel downstream AMPK targets and develop therapeutic techniques that target the enzyme to prevent and treat myocardial ischemia, cardiac hypertrophy and diabetes.
AMPK also shows potential as a drug target for cancer treatment because it may work as an antioxidant, modulating the levels of reactive oxygen species in tumor cells. Building on our understanding of these processes, my group has demonstrated that natural antioxidants extracted from Chinese herbal medicines inhibit the proliferation of tumor cells via related processes. We currently aim to determine these substances’ signaling targets in tumor cells and to develop cancer therapies based on natural products from herbal medicines.
Specialty/Research Focus:
Genomics and proteomics; Protein Function and Structure; Proteins and metalloenzymes
Research Summary:
Research in my laboratory is focused on: 1) structural and functional characterization of membrane protein enzymes involved in fatty acid and lipid metabolism; and 2) the development of tools for high-throughput structural characterization of membrane proteins.
Specialty/Research Focus:
Infectious Disease
Research Summary:
Respiratory tract bacterial pathogens
Vaccine development
Bacterial infection in chronic obstructive pulmonary disease
Haemophilus influenzae
Moraxella catarrhalis
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.
Specialty/Research Focus:
Microbial Pathogenesis; Molecular and Cellular Biology; Gene Expression; Regulation of metabolism
Specialty/Research Focus:
Toxicology and Xenobiotics
Research Summary:
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.
Research Summary:
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.
Specialty/Research Focus:
Neurodegenerative disorders; Apoptosis and cell death; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Neurobiology; Neuropharmacology; Protein Folding; Protein Function and Structure; Proteins and metalloenzymes; Signal Transduction; Toxicology and Xenobiotics
Specialty/Research Focus:
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
Research Summary:
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.
Specialty/Research Focus:
Microbial Pathogenesis; Molecular and Cellular Biology; Molecular genetics; Gene Expression
Research Summary:
Trypanosomes are members of the kinetoplastid protozoa, which cause enormous medical and economic distress in Third World countries. They are eukaryotic parasites which are the causative agents for diseases such as Sleeping Sickness, Leishmaniasis, and Chagas disease. In our laboratory, we study the parasitic trypanosome, Trypanosoma brucei. In addition to being of great medical and economic importance, T. brucei is an excellent model system for the study of posttranscriptional gene regulation, because regulation at the level of transcription is essentially absent in this organism. Our primary focus is on two RNA processing events in T. brucei: RNA editing and RNA turnover. A third related area of research is the mechanism by which posttranslational modification of RNA binding proteins by arginine methylation regulates RNA editing, trafficking, turnover, and trans-splicing.
RNA editing is a novel mechanism for regulating gene expression in which sequence information is added to mRNAs after transcription by specific uridine addition and deletion. The editing of mRNAs in T. brucei is so extensive that uridine insertions can double the size of the transcript. Editing generates translatable messages by creating the open reading frames as well as proper initiation and termination signals. The phenomenon is of fundamental importance in understanding how genetic information can be stored and processed. We are studying the mechanisms used by T. brucei to regulate editing of specific RNAs, particularly as they are differentially edited between life cycle stages. We identified the first RNA editing regulatory factor, a mitochondrial RNA binding protein termed RBP16. Genetic disruption of RBP16 in insect stage trypanosomes causes massive down-regulation of a specific subset of editing events. Currently, we are using a combination of biochemical and genetic approaches to elucidate the mechanisms by which RBP16 regulates editing of specific RNAs and to determine its regulatory scope throughout the trypanosome life cycle. Our approaches include gene knock-down of RBP16 and RBP16-associated proteins in both insect and mammalian life cycle stages, analysis of the biochemical effects of RBP16 on RNA editing in vitro, and yeast-two hybrid and TAP affinity chromatography approaches to identification of RBP16 binding partners. Future directions will involve the identification and characterization of additional RNA editing regulatory proteins.
The levels of translatable mRNAs are dictated by the balance between transcription rates and mRNA turnover rates. Because transcription is largely unregulated in T. brucei, the mechanisms by which mRNA turnover is controlled take on enhanced importance. We have identified two pathways for mRNA turnover in T. brucei mitochondria. One pathway is specific for polyadenylated RNAs and depends on the UTP concentration, while the second pathway is independent of the polyadenylation state of the RNA and nucleotide concentrations. We developed an in vitro RNA turnover system that allows us to directly examine the effects of specific 3? sequences on RNA degradation. We are also using this system as a starting point for biochemical purification of the proteins that catalyze and regulate RNA turnover pathways. In addition, we used a bioinformatics approach to identify trypanosome homologs of the yeast mitochondrial degradosome proteins DSS1 (an exoribonuclease) and SUV3 (and RNA helicase). Biochemical and genetic studies are underway to determine the roles of these proteins in turnover of the various classes of mitochondrial RNAs.
Methylation of arginine residues in proteins is a posttranscriptional modification whose important in areas such as signal transduction, RNA trafficking, mRNA splicing, and transcription is just recently becoming apparent. Interestingly, a very large percentage of proteins that undergo arginine methylation are RNA binding proteins. Given that gene regulation in trypanosomes relies so heavily on RNA processing, our hypothesis is that arginine methylation is especially important in these organisms. We showed that multiple proteins in T. brucei are subject to arginine methylation (including the mitochondrial RNA binding protein, RBP16). In addition, we identified two genes encoding the protein arginine methyltransferases (PRMTs) that catalyze this modification. Studies are currently underway to determine the effect of PRMT down-regulation in trypanosomes on growth rate as well as on specific RNA processing events. We are identifying novel PRMT substrates in T. brucei using both yeast two-hybrid and affinity chromatography methods. Finally, mutation of the methylated arginine residues in RBP16 will allow us to determine how this modification modulates the function and macromolecular interactions of this protein.
Specialty/Research Focus:
Neurodegenerative disorders; Apoptosis and cell death; Membrane Transport (Ion Transport); Proteins and metalloenzymes; Signal Transduction; Toxicology and Xenobiotics
Research Summary:
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.
Research Summary:
A SUNY Distinguished Professor & member of the UB faculty for more than 30 years, Dr. Rudin is a world-renowned expert in the field of medical physics. the quintessential interdisciplinary research scientist, Dr. Rudin is an international force in the development of a host of cutting-edge technology & methodology in the area of medical diagnostic & interventional imaging. He has won multiple awards for scientific excellence as well as awards for excellence in design, and is particularly well-known for his work in developing a solid state
x-ray image intensifier and his research in asymmetric stents, work with major theoretical and clinical implications for medical physics, biomedical engineering, and diagnostic radiology, as well as an immediate impact upon patient diagnosis and care, particularly in case of brain and heart treatment. The caliber, significance, and innovation of his research are demonstrated by the numerous grants he has received from the NIH.
Specialty/Research Focus:
Periodontics; Operative Dentistry; Oral Biology; Pediatric Dentistry
Research Summary:
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 proteins 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: http://dental.buffalo.edu/oralbiology/home.asp?f=shruhl
Research Summary:
Mucosal immunologist, with particular interests in immunoglobulin A, mucosal vaccines against bacterial infections, immunity to dental caries and to gonorrhea. Formerly a member of the large mucosal immunology group at the University of Alabama at Birmingham.
Specialty/Research Focus:
Infectious Disease
Research Summary:
Extraintestinal isolates of Escherichia coli
Urinary tract infection, pulmonary infection, bacteremia
Microbial pathogenesis
Vaccine development
Acinetobacter baumannii
drug targets
Klebsiella pneumoniae
Dr. Russo’s first research focus involves certain strains of Escherichia coli that are capable of causing a variety of infections outside of the intestine in both humans and domestic animals. Billions of health care dollars, millions of work-days, and hundreds of thousands of lives are lost each year to extraintestinal infections due to E. coli. A vaccine is not presently available to prevent these infections and treatment is becoming more problematic with increasing antimicrobial resistance. Studies have focused on: 1) identification of new virulence determinants, 2) E. coli-host interactions, and 3) vaccine development. Dr. Russo is also collaborating with Dr. Knight from Anesthesiology on the effects of E. coli lung infection and acid-particulate aspiration on acute lung injury.
The second focus is on the bacterium Acinetobacter, which was best known for causing health-care associated infections until a recent series of infections reported in U.S. service members injured in Iraq/Afghanistan. Particularly disconcerting is the degree of antimicrobial resistance possessed by these strains of Acinetobacter; with some being resistant to all antimicrobials tested. Therefore studies have begun to fill that void by logically identifying novel antimicrobial targets. To accomplish this goal Dr. Russo has been collaborating with Drs. DeTitta, Umland and Schultz from the Hauptman-Woodward Medical Research Institute. Targets are being identified using a genetic approach combined with in vitro and in vivo studies to prioritize target selection, followed by structural studies and in vitro fragment based lead screening. These studies are designed to develop new antibiotics active against Acinetobacter and other multi-drug resistant gram-negative bacilli. Dr. Russo is also collaborating with Dr. Campagnari from Microbiology on studies designed to understand biofilm formation in Acinetobacter, which in turn may lead to improved treatment or prevention of infection.
Most recently Dr. Russo has begun studying a new hypervirulent variant of Klebsiella pneumoniae (hvKP). hvKP is characterized and distinguished from traditional infections due to “classical” K. pneumoniae (cKP) by: 1) presenting as community-acquired hepatic abscess, 2) affecting patients lacking a history of hepatobiliary disease, and 3) a propensity for causing metastatic spread to distant sites in 11-80% of cases (e.g. eyes, central nervous system (CNS), & others). Metastatic spread is common for certain gram-positive pathogens such as Staph and Strep, but is uncommon enteric GNB (e.g. E. coli and cKP). The basis for this change is poorly understood. One of the goals of this proposal is to fill that knowledge gap by identifying novel or unrecognized pathogenic traits of hvKP that contribute to its hypervirulence. Compounding an already difficult situation, some cases of infection due to hvKP have been caused by multi-drug resistant (MDR) strains and as expected, outcome is worse with MDR strains or inappropriate treatment. Unfortunately there are virtually no new antimicrobial agents active against MDR-GNB in the pharmaceutical “pipeline”. The confluence of hypervirulence and MDR in hvKP has the potential to create a “post-antibiotic” scenario; similar to what was feared with methicillin resistant S. aureus (MRSA) but was never realized. Therefore, the second goal of this project is to fill that void by identifying antimicrobial targets in hvKP. These data will be important and unique, and will lay the foundation for understanding the biology of this new clinical variant and for the future of in vitro lead drug screening and structural based development.
Specialty/Research Focus:
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
Research Summary:
Research Interests:
My 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.
Specialty/Research Focus:
Internal Medicine; Immunology; Infectious Disease; Microbial Pathogenesis
Research Summary:
Areas of clinical and research interests
·NADPH oxidase as a critical regulator of host defense and inflammation
·Pathogenesis of invasive aspergillosis
·Role of innate immune responses in tumor immunology
The major interest of our lab is to study NADPH oxidase as a critical regulator of inflammation and host defense. NADPH oxidase is an emergency host defense pathway that is rapidly activated in response to certain microbial products, and converts molecular oxygen to superoxide anion and downstream reactive oxidant intermediates (ROIs). Chronic granulomatous disease is an inherited disorder of the NADPH oxidase characterized by severe bacterial and fungal infections (e.g., invasive aspergillosis) and by excessive inflammation. In addition to its critical host defense role, our lab, in collaboration with colleagues, found that NADPH oxidase also functions to restrain inflammation by modulating redox-sensitive innate immune pathways. NADPH oxidase also affects T-cell responses, including the balance between Tn17 and regulatory T-cells. We have an NIH grant to further elucidate mechanisms by which NADPH oxidase regulates inflammation.
We believe that our work has broad relevance to human diseases associated with inflammation, such as inflammation-induced injury and tumor immunology. Indeed, several of the pathways that NADPH oxidase regulates are important in tumorigenesis and the tumor microenvironment (e.g., NF-kB, Nrf2, IL-17, Tregs), and are potential therapeutic targets. In collaboration with colleagues, we are examining how NADPH oxidase influences tumor immunity.
Specialty/Research Focus:
Genomics and proteomics; Neurobiology; Neurodegenerative disorders
Research Summary:
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.
Specialty/Research Focus:
Dermatology; Autoimmunity; Gene Expression; Genomics and proteomics; Immunology
Specialty/Research Focus:
Genomics and proteomics; Molecular and Cellular Biology; Gene Expression
Research Summary:
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.
Research Summary:
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.
Research Summary:
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.
Specialty/Research Focus:
Microbiology; Gene Expression; Molecular and Cellular Biology; Signal Transduction
Research Summary:
We are interested in developing an integrated mechanistic view of how organisms coordinate the actions of their replication machinery with those of other cellular factors involved in DNA repair and damage tolerance. We utilize a combination of biochemical, biophysical, and genetic approaches to investigate the molecular mechanisms of DNA replication and DNA repair in Escherichia coli. 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.
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. We are particularly interested in determining the contribution of mutagenesis and DNA repair to clonal expansion and pathoadaptation of P. aeruginosa during colonization of cystic fibrosis airways.
Specialty/Research Focus:
Hematology; Internal Medicine; Oncology
Specialty/Research Focus:
Hematology; Oncology; Internal Medicine - General
Research Summary:
-Translational research focuses on three areas: the role of the BCR gene involved in chronic and acute leuke-mias, the involvement of cytokines and their signal transduction in leukemogenesis, and the development of immunotherapy for leukemia.
The BCR gene plays a crucial role in the pathogenesis of leukemias bearing the Philadelphia chromosome. Recently, we have shown that the Bcr protein, while residing mainly in the cytoplasm in quiescent cells, is associated with the chromosomes in mitotic cells. We hypothesize that Bcr has a role in both normal and leuke-mic cell division, and will investigate this hypothesis. Among other things, this might explain events occurring during Bcr-Abl-associated transformation, and differences between the distinct phenotypes in Bcr-Abl-associated leukemias.
Acute myeloid leukemia (AML) is a clonal disease often characterized by acquired somatic mutations. All chromosomal abnormalities in AML result in an arrest of maturation and accumulation of undifferentiated cells. We believe that molecular changes, produced by mechanisms unrelated to chromosomal aberrations, may be assisting in leukemogenesis. We ask whether truncated signal transducer and activator of transcription (STAT) proteins contribute to leukemogenesis. We have shown that most AML blasts express truncated STAT isoforms (STATb) more commonly than the full-length forms (i.e., STATa). These STATb forms, which lack a C-terminal transactivation domain, have been shown to exert a negative effect on cellular differentiation and hence on apoptosis. We have shown that samples from 21 of 27 AML patients express STAT3b and STAT5b. We also have shown that these forms are generated by a serine-dependent protease. We propose that b isoforms of STAT3 and STAT5 negate the action of the a isoforms and that their
expression serves to prevent induction of cytokine-responsive genes, as well as induce or amplify survival signals. We will characterize the serine protease responsible for generating the STATb forms in AML blasts, and study its regulation. Based on this information, it may be possible to tailor treatment of AML with different phenotypes.
To date, it is not known whether leukemia patients who are in long-term remission are capable of mounting a specific immune response to their disease. Such a mechanism has been described in animal models of leukemia but in the human system it was described only in malignant melanoma. In this study, the focus will be on T lymphocytes and antibodies that possess specificity for potential leukemic antigens. Individuals who have had leukemia in recent years and are now clinically-free of disease will be tested. T cells obtained by leukapheresis and serum will be tested against autologous leu-kemic blasts stored at the time of diagnosis. Then, T cell lines will be established that will be used to characterize the specific antigen(s) that caused their development.
Specialty/Research Focus:
Gene Expression; Infectious Disease; Microbial Pathogenesis; Microbiology; Molecular Basis of Disease; Molecular and Cellular Biology; RNA; Regulation of metabolism; Transcription and Translation
Research Summary:
Our laboratory uses molecular biological and biochemical approaches to study two projects focusing on the parasitic protozoan, Trypanosoma brucei. The first project centers on the mitochondrial ATP synthase of T. brucei. This protein complex couples the energy generated by the electron transport chain to the synthesis of ATP. In T. brucei we have shown that the ATP synthase is regulated through the life cycle of the organism by several unique mechanisms which appear to be different from the regulatory mechanisms for other mitochondrial proteins such as those in the electron transport chain. This regulation may be critical to understanding how this parasite responds to change in the environment due to the two host organisms (in this case, the tsetse fly and the cow). We have isolated the ATP synthase and have cloned several genes for component subunits of the complex. We have shown a differential regulation of these subunits at the level of mRNA stability and are now examining the specific sequences and
nucleic acid binding proteins involved in this regulation. We are using RNA interference to create genetic knock downs as a tool to understanding the role of the ATP synthase in the parasites survival in its hosts.
The second project, in collaboration with Dr. William Ruyechan, examines a pair of unique RNA binding proteins, p34 and p37, which are highly homologous to one another. We have shown that these proteins interact with 5 S rRNA and hypothesize that they act to chaperone the 5 S rRNA from the nucleus where it is synthesized by RNA polymerase III, to the nucleolus for assembly with other ribosomal components. We have also identified a family of nucleolar phosphoproteins, the NOPP44/46 proteins, that interact with the p34 and p37 proteins, and may assist in this process of 5S rRNA migration. The p34 and p37 proteins show developmentally regulated expression through the life cycle of T. brucei. Most interestingly, the regulation of the two proteins are exactly opposite one another making them an excellent target to examine developmentally regulated genes. Expression of the smaller of the two proteins, p34, is regulated by differential mRNA stability and we have found two AU rich sequence elements present in the 3‘
untranslated region of this transcript that may be responsible. These AU rich elements have been shown in higher eukaryotes to be involved in both transcript stability and translational regulation. In constrast, expression of the larger protein, p37, is regulated translationally, possibly by sequences in the 3‘ untranslated region as well. In addition, we have found that the p37 protein is specifically degraded in the procyclic stage of the parasite and are currently characterizing the protease responsible for this process.
In collaboration with Dr. Beatriz Garat, Universidad de la Républica, Dept. of Biochemistry, Montevideo, Uruguay, we are examining proteins which bind to dinucleotide repeats occurring in the intergenic regions of the genome of Trypanosoma cruzi. This project, which has been funded by the Fogarty Foundation, examines whether these repeats together with their cognate binding proteins may be involved in gene regulation in T. cruzi.
Specialty/Research Focus:
Behavioral pharmacology; Neuropharmacology; Toxicology and Xenobiotics
Research Summary:
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.
Specialty/Research Focus:
Neurodegenerative disorders; Pathophysiology; Cytoskeleton and cell motility; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Neuropharmacology; Signal Transduction
Research Summary:
My lab is focused on studying the mechanisms underlying the regulation of ligand-gated ion channels and synaptic transmission, and its implication in various brain disorders. Information processing in the central nervous system (CNS) is achieved by the interplay between chemical and electrical signals. Neurotransmitters (e.g. serotonin, dopamine, acetylcholine) and hormones (e.g. corticosteroid) influence CNS functions by regulating ion channels, which can produce short-term changes in membrane excitability and long-term changes in synaptic plasticity. Dysfunctions of these neuromodulators in specific brain regions have been implicated in the pathogenesis of various mental disorders, including Schizophrenia, depression and Alzheimer’s disease. One of our major goals is to understand how these neuromodulators regulate ligand-gated ion channels and synaptic transmission in prefrontal cortex, a key region controlling cognition and emotion.
Neuromodulators exert their actions through G protein-coupled receptors or nuclear hormone receptors. These receptors link to various intracellular signaling cascades, which potentially influence different ion channels in a specific and coordinated manner. We use a combination of multiple approaches to reveal signal transduction pathways mediated by neuromodulators. Specifically, electrophysiological techniques, such as whole-cell patch-clamp recordings in dissociated or cultured neurons and brain slices, are used to characterize the effect of neuromodulators on glutamate/GABA receptor channels and synaptic transmission. Biochemical and pharmacological approaches are used to identify the signaling molecules linking neuromodulators and channels. Molecular and immunocytochemical techniques are used to detect the expression, localization and trafficking of receptors, ion channels and signaling components in neurons. Moreover, animal models for neurological disorders are used to examine how the neuromodulator actions are altered in these pathological conditions. Our studies will provide knowledge on the molecular and cellular mechanisms underlying the regulation of synaptic transmission by neuromodulators, which is important for mental health and diseases.