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.
Reproductive Endocrinology; Apoptosis and cell death; Cell growth, differentiation and development; Endocrinology; Gene Expression; Molecular genetics; Signal Transduction; Toxicology and Xenobiotics; Vitamins and Trace Nutrient
My research and practice focuses on developing, promoting, and evaluating effective means of pharmacology instruction at the undergraduate, graduate, professional, and interprofessional levels. Developing a competency-based curriculum in pharmacology for students at all levels, I have incorporated specific instructional methods into existing core courses that has, in effect, taken a sometimes intimidating subject like pharmacology and presented it to students in manageable ways. Studies of the effectiveness of these methods are conducted in collaboration with professional societies, including ASPET and its Division of Pharmacology Education. Specific instructional methods in the study include: patient case presentations by professional students utilizing rubric descriptors of performance quality and 360 feedback; Pharm Fridays throughout the second year medical curriculum incorporating organized lists of pertinent drugs to recognize, student-oriented learning objectives, pharmacology study guides focusing on essential therapeutics, their indications, mechanisms of action, adverse drug reactions, and drug interactions; active participation clicker sessions with relevant board-style pharmacology questions; development of performance-based pharmacology questions within the multidisciplinary objective structured clinical exam (OSCE) taken by all DDS candidates; and video presentations demonstrating pertinent pharmacology topics such as medical sedation, use of emergency drugs in the clinic, and safe and effective means for pain management with interviews of clinical experts. These and other instructional methods in the study are highly rated by students and proven effective by outcomes on standardized exams. For the last several years, I have been co-director of the endocrine-reproductive biology module for second-year medical students. As an ongoing means to improve pharmacology instruction, I coordinated the recent survey of pharmacology instruction in the medical curriculum, assessing adequacy of pharmacology learning objectives, utility of various instructional methods, coverage of USMLE Step 1 pharmacology expectations, and incorporated mechanisms to improve instruction and medical student preparation in pharmacology. Other recent advancements include the launching of an online pre-professional undergraduate pharmacology course with all presentations fully accessible to persons with disabilities.
Cardiology; Cardiovascular Disease; Apoptosis and cell death; Cardiac pharmacology; Gene therapy; Genomics and proteomics; Molecular Basis of Disease; Stem Cells
As a SUNY Distinguished Professor, I am involved in the clinical, teaching and research programs is the Division of Cardiovascular Medicine at the University at Buffalo. I care for patients at the Gates Vascular Institute (GVI) of Buffalo General Medical Center (BGMC), the Buffalo VA Medical Center (VAMC) and I am a member of the UBMD clinical practice. My clinical areas of expertise are in diagnosing and caring for patients with coronary artery disease and heart failure. My research group conducts bench to bedside translational studies directed at advancing our mechanistic understanding of cardiac pathophysiology as well as developing new diagnostic and therapeutic approaches for the management of patients with chronic ischemic heart disease. Our ongoing areas of preclinical investigation apply proteomic approaches to identify intrinsic adaptive responses of the heart to ischemia and studies examining the ability of intracoronary stem cell therapies to stimulate endogenous cardiomyocyte proliferation and improve heart function. We are particularly interested in understanding how elevations in heart filling pressures and reversible ischemia lead to cardiomyocyte cell death and heart dysfunction. We also conduct basic and patient-oriented research to understand how chronic ischemia modifies the cellular composition and sympathetic innervation of the heart to help develop new approaches to identify patients at risk of sudden cardiac arrest from ventricular fibrillation using positron emission tomography in the UB Center for Biomedical Imaging. Our overall goal is to use advanced cardiac imaging to translate new applications between the bench and bedside in order to identify new imaging biomarkers of pathophysiological processes such as chronic myocardial ischemia and cardiac arrhythmogenesis. In addition to my laboratory investigation, I serve as the deputy director of the UB Clinical and Translational Science Institute (CTSI) and the director of the UB Translational Imaging Center. I am engaged in the cardiology profession at national and international levels, including study sections of the National Heart Lung and Blood Institute, professional guidelines committees and served as former president of the Association of Professors of Cardiology.
Neurology; Neurodegenerative disorders; Pathophysiology; Apoptosis and cell death; Cytoskeleton and cell motility; Molecular and Cellular Biology; Molecular genetics; Neurobiology; Protein Folding; Gene Expression; Transcription and Translation; Signal Transduction; Toxicology and Xenobiotics
My research is aimed at finding the cause and a cure for Parkinson’s disease. Parkinson’s disease (PD) is defined by a characteristic set of locomotor symptoms (rest tremor, rigidity, bradykinesia and postural instability) that are believed to be caused by the selective loss of dopaminergic (DA) neurons in substantia nigra. The persistent difficulties in using animals to model this human disease suggest that human nigral dopaminergic neurons have certain vulnerabilities that are unique to our species. One of our unique features is the large size of the human brain (1350 grams on average) relative to the body. A single nigral dopaminergic neuron in a rat brain (2 grams) has a massive axon arbor with a total length of 45 centimeters. Assuming that all mammalian species share a similar brain wiring plan, we can estimate (using the cube root of brain weight) that a single human nigral dopaminergic neuron may have an axon with gigantic arborization that totals 4 meters. Another unique feature of our species is our strictly bipedal movement, which is affected by Parkinson’s disease, in contrast to the quadrupedal movement of almost all other mammalian species. The much more unstable bipedal movement may require more dopamine, which supports the neural computation necessary for movement. The landmark discovery of human induced pluripotent stem cells (iPSC) made it possible to generate patient-specific human midbrain dopaminergic neurons to study Parkinson’s disease. A key problem for dopaminergic neurons is the duality of dopamine as a signal required for neural computation and a toxin as its oxidation produces free radicals. Our study using iPSC-derived midbrain dopaminergic neurons from PD patients with parkin mutations and normal subjects shows that parkin sustains this necessary duality by maintaining the precision of the signal while suppressing the toxicity. Mutations of parkin cause increased spontaneous release of dopamine and reduced dopamine uptake, thereby disrupting the precision of dopaminergic transmission. On the other hand, transcription of monoamine oxidase is greatly increased when parkin is mutated. This markedly increases dopamine oxidation and oxidative stress. These phenomena have not been seen in parkin knockout mice, suggesting the usefulness of parkin-deficient iPSC-derived midbrain DA neurons as a cellular model for Parkinson’s disease. Currently, we are using iPS cells and induced DA neurons to expand our studies on parkin to idiopathic Parkinson’s disease. We are also utilizing the molecular targets identified in our studies to find small-molecule compounds that can mimic the beneficial functions of parkin. The availability of human midbrain DA neurons should significantly speed up the discovery of a cure for Parkinson’s disease.
Apoptosis and cell death; Inherited Metabolic Disorders; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Regulation of metabolism; Transgenic organisms; Vision science
Our lab is focused on studies of retinal degenerations caused by metabolic defects, particularly dyslipidemias involving defective cholesterol metabolism (e.g., Smith-Lemli-Opitz syndrome), using pharmacological and transgenic animal models. Current studies are focused on the role of lipid and protein oxidation in the underlying mechanisms of photoreceptor cell death in such retinal degenerations, using a combination of genomic, proteomic, and lipidomic approaches.
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.
Apoptosis and cell death; Bioinformatics; Endocrinology; Gene Expression; Gene therapy; Genomics and proteomics; Immunology; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; RNA; Viral Pathogenesis
Dr. Mahajan has established herself as an investigator in the area of neuropathogenesis of HIV-1 in the context of drug abuse. She has established 2D and 3D Blood Brain Barrier (BBB) models, that allow studying mechanisms of BBB pathophysiology, examine BBB integrity and evaluate permeability of neurotherapeutics across the BBB. She investigates the role of a unique key signaling molecule in the dopaminergic pathway called DARPP-32, that impacts drug addiction, depression and other neurological disorders. Her focus has always been on collaborative, interdisciplinary partnerships between various Departments within UB that include the Institute of Lasers, Photonics and Biophotonics, Research Institute of Addiction, Dept of Computer Science and Engineering, Dept of Pharmaceutical sciences, Dept of Oral Biology and the Department of Bioengineering and also multiinstitutional collaborations with University of Rochester Medical Center and SUNY Albany. This inclusive strategy has facilitated the emergence of a robust, innovative clinical translational research program that continues to grow steadily. Dr Mahajan has obtained independent research funding from NIDA, NSF iCorp, Pharmaceuticals like Pfizer, Shire, Global- CRDF, US- Fulbright and other Private Foundations such as Dr. Louis Skalrow Memorial trust. Dr. Mahajan is Director of Research of the Division of Allergy, Immunology & Rheumatology. She supervises the research training of the Allergy fellows, Medical residents, graduate and undergraduate students. Dr. Mahajan has presented her research work at National and International conferences and was an invited speaker at several seminars and colloquiums. She has authored over 108 publications in several top quality peer reviewed journals and has thus demonstrated a high level of scholarly productivity. She is a reviewer and an adhoc member of the editorial board of several journals in her field. The following is a brief synopsis of her research interests. HIV neuropathogenesis in the context of drug abuse: We proposed that Opiates act as co-factors in the pathogenesis of HIV-1 infections by directly suppressing immune functions of the host through interactions with mu-opioid receptors on lymphocytes. Exacerbation of HIV encephalopathy (HIVE) is observed with opiate abuse. The mechanisms underlying HIVE are currently undetermined however, they likely to include the generation of endogenous neurotoxins combined, perhaps synergistically, with bioreactive HIV-1 envelope proteins. We believe that these proposed mechanisms may work through a common signal transduction mechanism activating dopamine D1 receptors in the nucleus accumbens of the brain. Opiate abuse by HIV-1 infected subjects may exacerbate the progression of HIVE as a consequence of the combined effects of HIV-1 induced neurotoxins plus opiate induced increases in the D1 receptor activation. We hypothesize that the dopaminergic signaling pathway is the central molecular mechanism that integrates the neuropathogenic activities of both HIV-1 infections and the abuse of opiate drugs. In this context our investigation is focused on the DARPP-32 signalling pathway. Addictive drugs act on the dopaminergic system of the brain and perturb the function of the dopamine- and cyclic-AMP-regulated phosphoprotein of molecular weight 32 kD (DARPP-32). DARPP-32 is critical to the pathogenesis of drug addiction by modulating both transcriptional and post-translational events in different regions of the brain. DARPP-32 is localized within neurons containing dopamine receptors and is a potent inhibitor of another key molecule in the dopaminergic signaling pathway, protein phosphatase 1 (PP-1). We propose that the sustained silencing of DARPP-32 gene expression using specific siRNA delivered to the brain is an innovative approach for the treatment of drug addiction. The specific challenge of the proposed project is the non-invasive delivery of biologically stable, therapeutic siRNA molecules to target cells within the brain. We are developing biocompatible nanoparticles to both protect DARPP-32 specific siRNA against degradation and deliver it from the systemic circulation across the BBB to specific dopaminergic neurons in the brain of patients with opiate addictions. BBB Research: While examining neuropathogenesis of HIV, we became interested in the role of the blood-brain barrier (BBB) in HIV neuropathogenesis with the objective of developing therapeutic interventions to prevent and limit the progression of HIV associated neurological disease. The blood-brain barrier is an intricate cellular system composed of vascular endothelial cells and perivascular astrocytes that restrict the passage of molecules between the blood stream and the brain parenchyma. The in-vitro BBB models allow examining permeability of virus, effects of drugs of abuse on BBB permeability, mechanisms of BBB transport, and tight junction modulation. Our goal remains to determine the impact of current and potential CNS antiretrovirals, psychopharmacologic, and other medications on the integrity of the BBB in HIV associated neurological disorder and other neurodegenerative diseases. Additionally, we also investigate mechanisms that underlie drugs of abuse induced neuronal apoptosis. Systems biology approach: We expanded our investigation to include functional genomic/proteomic NGS analyses that allowed characterization of gene/ protein modulation in response to a drug stimulus or under a specific disease condition. We developed an expertise in these large-scale genomic and proteomic studies and the genomic studies helped identify key genes that underlie molecular mechanisms in drug addiction, HIV diseases progression, and allowed examination of the interplay of genes and environmental factors. The proteomic studies confirmed the presence of specific proteins that regulate key biological processes in drug addiction and HIV diseases progression. Recently, We have expanded my research program to include microbiome analyses and incorporated the utility of the computational drug discovery platform (CANDO) model that allows studying interaction between protein structures from microbiome genomes and determine the interactions that occur between them and small molecules (drugs and human/bacterial metabolites that are already a part of or continue to be added to the CANDO library. Using the CANDO Platform we are able to do the hierarchical fragment-based docking with dynamics between those compounds/drugs and the microbiome proteins/proteomes to determine which ones of the drugs and metabolites will work most efficaciously in patients using specific drugs. NanoMedicine: We have developed a strong program in nanomedicine and have initiated several interdisciplinary clinical translational research focused collaborations that include 1) Nanotechnology based delivery systems to examine antitretroviral transport across the BBB; 2) Nanotherapeutics using siRNA/Plasmid delivery to specific regions in the brain to target various genes of interest specifically those pertaining to the dopaminergic pathway that result in the modulation of behavioral response which we observed in animal models of addiction/depression; 3) Biodistribution studies of various nanotherapeutic formulations using PET small animal imaging. Additionally, We are also focused on exploring epigenetic mechanisms that under drug addiction and mechanisms that underlie oxidative stress in neurodegenerative diseases.
Apoptosis and cell death; Cell growth, differentiation and development; Cytoskeleton and cell motility; Immunology; Signal Transduction; Stem Cells
My independent research at The University at Buffalo focuses on targeting the mammary gland microenvironment by evaluating cellular and tissue responses during specific developmental windows of mammary gland remodeling including puberty, the period of hormonal withdrawal during estrous cycling, or post-lactational involution. My choice to focus on discrete times of development for chemopreventive intervention, rather than long-term (and often life-time) intervention, represents a unique approach of short-term exposure at critical points of mammary gland development. Our goal is to allow women to bypass the need for lifelong compliance to a chemopreventive diet or drug regimen in order to attain lifelong protection against breast cancer. Developmentally targeted dietary interventions being investigated in our lab include continuous administration of oral contraceptives, dietary exposure to conjugated linoleic acid, and ethanol.
Drug abuse; Apoptosis and cell death; Molecular and Cellular Biology; Neurobiology; Signal Transduction; Toxicology and Xenobiotics
My laboratory is focused on understanding the molecular and cellular actions of drugs of abuse such as ethanol and hallucinogens such as lysergic acid diethylamide (LSD). This information is a requisite step in the ultimate development of therapeutic interventions to alleviate the major healthcare and social burden associated with use and abuse of these drugs. In addition, these drugs provide an avenue to explore the basic workings of the brain under pathological conditions that are manifested as various psychiatric disorders. Previous studies, in collaboration with Dr JC Winter in the Dept of Pharmacology and Toxicology at UB, have investigated the roles of the various serotonin receptors subtypes and their associated signaling pathways as well as glutamatergic neurotransmission in the subjective effects of LSD-type hallucinogens. Our other studies have been aimed at understanding the adverse developmental effects of ethanol exposure that result in the fetal alcohol spectrum disorders with the fetal alcohol syndrome (FAS) as the most severe manifestation. Using zebrafish and neuronal cells in culture as model systems, my laboratory in collaboration with Dr CA Dlugos in the Dept of Pathology and Anatomical Sciences at UB have investigated the morphological and histological changes associated with ethanol exposure during different developmental stages as well as the mechanisms by which developmental ethanol exposure causes neuronal loss. Currently, we are investigating the neurotoxic interaction of ethanol with pesticides. Because of the wide-spread use of pesticides, people are continually exposed both voluntarily and involuntarily to an array of toxic chemicals. In addition, since consumption of alcohol is pervasive in our society with a very high prevalence of alcohol use and abuse, it is extremely likely that people with be co-exposed to both ethanol and pesticides. Because simultaneous or sequential exposure to multiple chemicals can dramatically modify the ensuing toxicological responses, we are using both in vitro (e.g., cells in culture) and in vivo (e.g., zebrafish) model systems to begin assessing the possible health risk of co-exposure to ethanol and pesticides. Using the herbicide paraquat, which is widely used throughout the world, as a test compound, we have found that ethanol synergistically increases the in vitro neurotoxicity of this pesticide. Our efforts are now aimed at ascertaining whether a similar interaction occurs in vivo as well as determining the molecular mechanism responsible for this synergistic neurotoxicity. Teaching is a naturally complement to research. Accordingly, I have also been engaged in efforts to both improve how we provide the knowledge base to our undergraduate, graduate, and professional students, and also how we help students learn to integrate and apply this information in problem-solving at the clinical and basic science levels. Efforts include: 1. using “clickers” in large class formats to assess student’s understanding of the material and well as provide each student instantaneous feedback for their own self-assessment; 2. using cases studies and a small group learning format; and 3. Having students write short grant proposals based upon the current literature as well as reviewing and critiquing their classmate’s proposals.
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.