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.
Cardiology; Cardiovascular Disease; Regulation of metabolism
My clinical activities as a noninvasive cardiologist primarily take place at the Buffalo VA Medical Center (VAMC). My responsibilities include attending on the inpatient cardiology consultation service and interpreting echocardiograms, stress tests and electrocardiograms (EKGs). My research career initially focused on translational research using porcine models to investigate physiologic and metabolic adaptations that result from acute and chronic myocardial ischemia (chronically stunned and hibernating myocardium). These preclinical investigations have led to clinical research, including the recent completion of an NIH-sponsored clinical trial. This trial, on which I am the co-principal investigator with John M. Canty, Jr., MD, proved that the presence of sympathetically denervated myocardium quantified by positron emission tomography can predict the risk of sudden death in patients with ischemic cardiomyopathy. I am in the process of extending these findings to the clinical management of patients with implantable cardiac defibrillators. My work as a physician-scientist has included serving on numerous research-related oversight committees and as a peer reviewer for multiple national, regional and local committees. I have been funded by the National Institutes of Health (NIH), the Department of Veterans Affairs and the American Heart Association to conduct a variety of investigator-initiated research projects. Medical education is a critical component of my professional life. Nearly all of my clinical and research activities are performed in conjunction with the education of fellows in cardiovascular diseases, residents in internal medicine and medical students. I facilitate small group sessions for second-year medical students in Cardiovascular Physiology for which I have earned several commendations for teaching excellence; I am gratified to have participated in the education of hundreds of young physicians. I have also published dozens of abstracts and manuscripts with various levels of trainees, giving them the opportunity to grow as physician-scientists while at the same time advancing medical knowledge.
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.
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.
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.
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.
Genomics and proteomics; Molecular and Cellular Biology; Regulation of metabolism; Toxicology and Xenobiotics
Dr. David Shubert has been at the University at Buffalo since 2006. He received is B.S in Pharmacy from Duquesne University and a Ph.D from the University at Buffalo. His research interests include the mechanism by which environmental chemicals initiate and promote cancer. He is the Assistant Dean for Biomedical Undergraduate Education and teaches pharmacology, toxicology and cardiovascular physiology. Dr. Shubert accepts undergraduate students interested in pursuing research in his areas of interest. He is an active member of the Society of Toxciology.
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.
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.
Cytoskeleton and cell motility; Genomics and proteomics; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Pathophysiology; Regulation of metabolism
1. Mechanism and regulation of gastric acid secretion: Regulation of gastric acid secretion is the major treatment of many GI diseases including GERD, gastric, duodenal and esophageal ulcers. The spending in treating these conditions is substantial. The gastric parietal cell, lining the lumen of the stomach, is responsible for the secretion of isotonic HCl (0.15M) into stomach. One ATP is consumed for every proton secreted into the stomach lumen and a lot of proton pump (H,K-ATPase, the alpha and beta subunits of this enzyme were discovered in 1967(1) and 1990(2)) is required for this job. To accommodate these many proton pumps, the apical plasma membrane, in the resting state, is expanded in the form of numerous invaginations which express relatively short microvilli, and a large compartment of cytoplasmic membranes, commonly called tubulovesicles, fully loaded with proton pumps. Upon stimulation by hismatine initiated PKA signaling, these tubulovesicles traffic to and fuse with apical membrane, forming densely packed microvilli comparable to those found on the brush border membrane of small intestine. This intracellular trafficking and fusion events bring proton pumps to their post for active acid secretion. In time, these proton pumps are brought back into the cytoplasm (by way of endocytosis) for a reliable mechanism to turn off acid secretion. Although the membrane recycling theory was raised a long time ago(3), there are still many major gaps in the understanding of the mechanism for the regulation of acid secretion, which are the research interests of our laboratory. Techniques employed include isolation and primary culture of gastric parietal cells, measurement of acid secretion, fractionation of different membranes by differential and gradient centrifugation. 2. Using gastric parietal cell model to study general cell biological questions: how membrane trafficking is regulated by small G-proteins, how filamentous actin supports the dynamic change of microvilli on apical membrane. The parietal cell has a remarkably large volume of intracellular membrane trafficking adapted to the elegant mechanism for the regulation of acid secretion. This means that this cell is abundant in those protein machineries required for membrane trafficking and fusion, exocytosis and endocytosis. For instance, no other cell type expresses the amount of syntaxin3 found in parietal cell. Therefore, parietal cell is the top choice for elucidating many of the core questions in cell biology. Techniques used to attack these questions include immunoabsorption, differential ultra-centrifugation, IMAC, 2D-electrophoresis, LC-MSMS, and confocal microscopy. 3. Pathogenesis of Nonalcoholic Steatohepatitis (NASH) - NASH research is funded by the Peter and Tommy Fund. NASH is a disease of the liver that is associated with obesity and adult onset, or type II, diabetes. NASH is not a benign disease. Many people with NASH have a shorter life expectancy than those who no not have NASH. NASH is associated with cirrhosis and is the third most common reason for liver transplantation in adults. No one knows what causes NASH, but it is known that in obese people there is increased fat in the liver. In addition to fat, cells that cause inflammation are found in the liver in patients with NASH. It is thought that these inflammatory cells may cause liver damage that results in fibrosis, cirrhosis and ultimately liver failure. The purpose of this research is to understand the relationship between obesity and the molecular factors that control inflammation so the interaction of the two can be better understood and treatments developed. NASH and alcoholic steatohepatitis share many histological features. Both NASH and alcoholic steatohepatitis patients exhibit macrovesicular and microvesicular fat in hepatocytes. The number and size of Mallory bodies, and the pattern of pericellular fibrosis are also indistinguishable between two disease groups. Previous studies suggested that intestinal bacteria produced more alcohol in obese mice than lean animals. Therefore, we hypothesized and provided the first molecular evidence that alcohol metabolism contributes to the pathogenesis of NASH (Baker et al, 2010). Fatty liver is a prerequisite for the development of NASH. The homeostasis of hepatic lipid depends on the dynamic balance of multiple metabolic pathways. Previous studies focusing on individual pathway or enzyme drew conflicting conclusions on the molecular mechanism for the accumulation of lipid in hepatocytes. With a high through-put technique, we compared all the major pathways in parallel. We are expecting to publish the exciting results in the near future. Oxidative stress is believed to be a major factor mediating the transition from simple steatosis to NASH. The prevention or mitigation of oxidative stress in patients with simple steatosis could prevent NASH. Our current research examines two facets of this problem: 1) what are the molecular mechanisms causing oxidative stress; 2) what are the molecular mechanisms that our body take to fight oxidative stress. Many novel findings have been observed in the lab and we are in the process of confirming these observations. 4. Pathogenesis of Inflammatory Bowel Diseases (IBD): The etiology of IBD is unknown, but a body of evidence from clinical and experimental observation indicates a role for intestinal microflora in the pathogenesis of this disease. An increasing number of both clinical and laboratory-derived observations support the importance of luminal components in driving the inflammatory response in Crohn‘s disease. Members of the Toll-like receptor family are key regulators of both innate and adaptive immune responses. These receptors bind molecular structures that are expressed by microbes but are not expressed by the human host. Activation of these receptors initiates an inflammatory cascade that attempts to clear the offending pathogen and set in motion a specific adaptive immune response. Defects in sensing of pathogens or mediation of the inflammatory cascade may contribute to the pathophysiology of disease and injure the host by activating a deleterious immune response, such as in inflammatory bowel disease. The focus of this research is to identify specific toll-like receptor mutations that may be associated with the development of inflammatory bowel disease.