Apoptosis and cell death; Cell Cycle; Cytoskeleton and cell motility; Gene Expression; Genomics and proteomics; Molecular Basis of Disease; Molecular and Cellular Biology; Signal Transduction
One third of our tissue mass is extracellular matrix (ECM). The ECM provides structural support for cells in tissues and varies from being stiff like bone to soft like skin. Importantly, the stiffness of the ECM affects how cells proliferate and migrate and this can be changed by injury or disease. My research is in blood vessels and particularly in arterial stiffening, which is a significant risk factor for the progression of cardiovascular disease, (leading worldwide cause of death). While medications reduce hypertension and cholesterol, none specifically treat arterial stiffness. My lab will identify what happens to cells when arteries become stiffened and determine how this contributes to cardiovascular disease. To understand how arterial stiffening affects cells, we will use mouse and cellular models to mimic the stiffening process in patients. We believe that cells within a stiffer matrix overproduce certain proteins that lead to uncontrolled cell growth, which then begets even more stiffening. Identifying and understanding the proteins in these pathways will allow the development of drugs to counteract their function. Our research will bring fundamental new knowledge about arterial stiffness and lead to new medications that help reduce a key cause of cardiovascular disease.
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
I am an Associate Professor in the Department of Pharmacology & Toxicology of the School of Medicine and Biomedical Sciences. I have a secondary appointment as Adjunct Associate Professor in the Department of Oral Biology in the School of Dental Medicine. My research interests focus on the study of how hormones and nutrients affect cell growth, differentiation, and survival. I study these processes in bone osteoblasts and breast normal epithelial cells as well as cancers of both tissues. I have discovered how natural estrogens as well as dietary phytochemicals sustain osteoblast longevity and contribute to bone growth. In collaboration with Dr Atif Awad of the University at Buffalo School of Public Health, I have identified dietary factors that inhibit the growth of cancers of the prostate and breast. We have published primary research papers, significant review articles, and two books entitled "Nutrition and Cancer Prevention" and Adipose Tissue and Inflammation".
Cardiology; Cardiovascular Disease; Apoptosis and cell death; Cardiac pharmacology; Gene therapy; Genomics and proteomics; Molecular Basis of Disease; Stem Cells
As chief of the Division of Cardiovascular Medicine at UB, I am responsible for the clinical, teaching and research programs related to adult patients with heart disease. I care for patients at the UBMD Internal Medicine practice group in Amherst, the Gates Vascular Institute (GVI) of Buffalo General Medical Center (BGMC) and the Buffalo VA Medical Center (VAMC). My clinical areas of expertise are in diagnosing and caring for patients with coronary artery disease and heart failure. My research group conducts translational studies directed at advancing our mechanistic understanding of cardiac pathophysiology as well as developing new diagnostic and therapeutic approaches for the management of patients with chronic ischemic heart disease. Our ongoing areas of preclinical investigation apply proteomic approaches to identify intrinsic adaptive responses of the heart to ischemia and studies examining the ability of intracoronary stem cell therapies to stimulate endogenous cardiomyocyte proliferation and improve heart function. We also conduct basic and patient-oriented research to understand how reversible ischemia modifies the cellular composition and sympathetic innervation of the heart to help develop new approaches to identify patients at risk of sudden cardiac arrest from ventricular fibrillation. In addition to my laboratory investigation, I serve as the deputy director of the UB Clinical and Translational Research Center (CTRC) and the director of the UB Translational Imaging Center. The Translational Imaging Center offers researchers opportunities to perform multimodality research imaging using PET molecular imaging, high-field magnetic resonance imaging (MRI) and X-ray computed tomography (CT). Our overall goal is to use advanced cardiac imaging to translate new applications between the bench and bedside in order to identify new imaging biomarkers of pathophysiological processes such as chronic myocardial ischemia and cardiac arrhythmogenesis. I am engaged in the cardiology profession at national and international levels, including as former president of the Association of Professors of Cardiology.
Apoptosis and cell death; Molecular Basis of Disease; Neurobiology
Professional Summary: The research in my laboratory has been focused on the effects of chronic ethanol abuse on aging neurons and the effects of ethanol on development of neuronal systems. These investigations are associated with major socioeconomic issues that will become more pronounced with time. For example, alcoholism in the elderly will become more pronounced as the alcohol-drinking baby boomer generation reaches old age. In addition, alcohol consumption during pregnancy remains the number one cause of mental retardation in the western world. In our aging and alcohol studies, extensive investigation of the Purkinje neuron (PN) of the cerebellar cortex have demonstrated that dendritic regression accompanies chronic ethanol consumption in aging Fischer 344 rats. Dendritic regression in PN alters synaptic transmission from the cerebellum, the major brain center for coordination. Further ethanol-induced alteration of regressing dendrites include dilation of the smooth endoplasmic reticulum (SER), a major calcium homeostatic component, and the formation of degenerating structures in dendrites of Purkinje neurons following chronic ethanol consumption in aging rats. These morphologic changes have been recently shown to be accompanied by decreased levels of the SERCA 2b pump which pumps calcium back into the SER following an action potential. Homeostasis between uptake and release of calcium from the SER is essential for cell health as uncontrolled release of calcium results in activation of a myriad of cellular pathways and cell death. Current investigations in the laboratory as focusing on the role ATF6 and caspase 12, both residents of the SER, in the development of ethanol-induced SER stress as a result of chronic ethanol consumption. Future investigations will include other ethanol-induced alterations to calcium homeostatic systems and the role of ethanol-induced alterations in epigenetics in decreases in calcium buffering mechanisms. The fetal alcohol study has focused on the effects of ethanol on the eye and the heart in the zebrafish model. Zebrafish are good models for developmental studies because they are transparent the short developmental period of three days between fertilization and hatching. Early investigations in collaboration with Dr. Richard Rabin established that the zebrafish was sensitive to ethanol and that the sensitivity was dose and strain dependent. Later studies focused on morphological and pharmacological assessment of ethanol-induced alterations to the heart and eye using pharmacologically relevant effects of ethanol. Current plans include focus on determining the mechanisms of ethanol’s actions on retinal ganglion cells and dopaminergic centers in the zebrafish.
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 initiated several new projects that investigate the role of a unique key signaling molecule in the dopaminergic pathway 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 and the Department of Bioengineering. This inclusive strategy has facilitated the emergence of a robust, innovative clinical translational research program for our Division that continues to grow steadily. Dr Mahajan has obtained independent research funding from NIDA, the pharmaceutical Pfizer, US- Fulbright and other Private Foundations such as Dr. Louis Skalrow Memorial trust to conduct some of these research projects. 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 95 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. We evaluated and validated both the 2 and 3 dimensional human in-vitro BBB models in my laboratory, that allowed 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 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: Over the last couple of years, We have become increasingly interested in nanomedicine and have developed 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 includes a phosphor protein called “DARPP-32”. Targeting various key genes in the dopaminergic pathway results 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.
Neurodegenerative disorders; Apoptosis and cell death; Membrane Transport (Ion Transport); Proteins and metalloenzymes; Signal Transduction; Toxicology and Xenobiotics
Dr. Jerome Roth‘s research interests over the past several years have focused on the mechanism of action of manganese in producing neuronal cell death. Manganese is an essential mineral that at high concentration acts as a neurotoxin which produces a Parkinson-like syndrome. Although the identified brain lesions associated with manganism differ from those of Parkinson’s disease, there is increasing evidence that chronic exposure to Mn correlates with increased susceptibility to develop Parkinsonism. Current studies are focused on characterizing the signal transduction pathways stimulated by manganese and to determine whether they also play a role in the toxic actions of this divalent cation. As part of this project we are also investigating the transport mechanisms by which manganese is taken up into cells. We have focused our studies on the divalent metal transporter (DMT1) and its role in the transport of manganese and other divalent cations. We are currently studying the transcriptional and post-translational factors that regulate its expression in vivo. Preliminary studies have linked DMT1 expression to the protein, parkin, mutations in which lead to early onset of Parkinson‘s disease. Whether other gene linked to Parkinsonism are also associate with development of manganism is the current focus of my research. Current studies in my laboratory focus on how other early and late genes associated with Parkinson’s disease can influence Mn toxicity as these studies will provide a basis for the comorbidity between manganism and Parkinson’s; the manipulation of this mechanism may therefore provide new prophylactic and/or management treatment options for Parkinson’s disease.
Cardiology; Cardiovascular Disease; Internal Medicine; Apoptosis and cell death; Cell Cycle; Cell growth, differentiation and development; Gene therapy; Stem Cells
I am a researcher with formal training and practice in both general and interventional cardiology. My research expertise is in coronary physiology and physiological studies in large animals with ischemic heart disease. Based on my background, my research is focused on therapeutic approaches to effect cardiac regeneration in large animals with acute and chronic ischemic heart disease. In my laboratory, I use a preclinical porcine model of hibernating myocardium with chronic left anterior descending (LAD) coronary artery occlusion and collateral-dependent myocardium or infarcted myocardium caused by coronary ischemia-reperfusion. I have addressed the problem with several different therapeutic approaches involved in gene therapy, pharmacological and stem cell therapies. We routinely perform physiological studies on these porcine models with quantitative analyses of myocardial morphometry and immune-histochemical analyses. The information we have collected in completed work demonstrates remarkable functional recovery and myocyte regeneration in the adult porcine heart. Intracoronary adenoviral gene transfer with fibroblast growth factor (FGF-5), the HMG-CoA inhibitor pravastatin and intracoronary mesenchymal stem cells (MSCs) all stimulate the proliferation of endogenous cardiac myocytes and, to some extent, generate new myocytes and vessels. Our current work is focused on understanding the regenerative capability of cardiosphere-derived cells (CDCs) originating from heart tissue in acute or chronic ischemic myocardium. The result of this work will play an important role in advancing the care of many patients with acute and chronic ischemic heart disease. In my laboratory, I mentor research fellows through their rotation. Fellows who work in my laboratory have the unique opportunity of being exposed to large animal experimentation and learning skills related to it--in physiology and coronary angiography, as well as computed tomography (CT) and magnetic resonance imaging (MRI) techniques. Under my supervision, fellows also may work on independent projects and learn about cell biology and molecular biology, with the chance to present at international meetings and to publish as an author in international journals.
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.