Addictions; Drug abuse; Behavioral pharmacology; Gene therapy; Molecular and Cellular Biology; Neurobiology; Gene Expression; Neuropharmacology
My laboratory seeks to understand the neurobiology of motivation and how these systems can be "highjacked" by abused substances. Substance abuse and addiction are wide-spread problems that have an enormous economic and emotional toll. Reports indicate that it costs the US upwards to $600 billion a year to deal with the health and criminal consequences and loss of productivity from substance abuse. Despite this, there are few effective treatments to combat this illness. The brain has natural systems responsible for motivating an organism to participate in behaviors that are necessary for survival, such as eating, exercise and reproduction. These same brain regions are highly sensitive to drugs of abuse, including cocaine, heroin and marijuana. My laboratory seeks to understand how these brain regions are affected by exposure to abused drugs, and in particular how the motivation to take drugs is altered by various molecular mediators in the neurons on these regions. The two basic questions we are interested in are 1) how projections from the cortex to the striatum influence drug seeking behaviors, and 2) how neurotransmitter receptors, particularly dopamine and cannbinoid receptors in these regions influence drug seeking. Our technical approaches include a number of basic behavioral models including measurements of locomotor activity, catalepsy, conditioned place preference and drug self-administration. In order to probe the circuitry of these brain regions, we use a number of advanced molecular techniques to activate and inactivate neuronal populations including optogenetics and artificial receptors. We probe the molecular pathways within the neurons by over expressing genes or knocking down expression using RNA interference. Gene delivery is accomplished using recombinant adeno-associated virus (rAAV) and several projects in the laboratory focus on improving this approach and exploring potential gene therapy applications for these vectors. The ultimate goal is to understand the basic neurobiology and molecular biology of addiction in order to develop more effective treatments for addiction.
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.
Addictions; Drug abuse; Behavioral pharmacology; Cytoskeleton and cell motility; Gene Expression; Gene therapy; Neurobiology; Neuropharmacology; Signal Transduction; Transcription and Translation
Drug addiction is a disabling psychiatric disease leading to enormous burdens for those afflicted, their friends and family, as well as society as a whole. Indeed, the addict will seek out and use illicit substances even in the face of severe negative financial, family and health consequences. It is believed that drugs of abuse ultimately “hijack” the reward circuitry of the CNS leading to cellular adaptations that facilitate the transition to the “addicted” state As is the case with both rodent models of drug taking, and well as throughout the global human population, not all individuals exposed to drugs of abuse will meet the classical definition of being truly “addicted”. We are looking at how molecular and behavioral plasticity mediates susceptibility to drug abuse and relapse like behaviors.
Neuroimmunology; Behavioral pharmacology; Gene therapy; Immunology; Molecular and Cellular Biology; Molecular Basis of Disease; Neurobiology; Gene Expression; Signal Transduction; Protein Function and Structure; Neuropharmacology
My research spans three interrelated fields: chronic pain, depression and inflammation. Experiments in my laboratory focus on how brain-derived pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF), function as modulators of brain-body interactions during neuropathic pain and how brain-TNF is involved in the mechanism of action of antidepressant drugs. My overall goal is to advance knowledge of, and therapeutic efficacy for pain, depression, neuro-inflammation and drug addiction. This research is based on my earlier work showing that neurons produce the pro-inflammatory cytokine TNF and that the production of TNF by macrophages is regulated by neurotransmitters. Cytokines and neurotransmitters are principal signaling molecules that mediate bidirectional communication between the nervous and immune systems--the crosstalk important in maintaining homeostasis. Consequently, aberrant production of either of these two classes of mediators could profoundly affect signaling by the other, thereby impacting health. A shift in balanced cytokine-neuron interactions that regulate neurotransmitter release in the central nervous system (CNS), and that have potential behavioral consequences, manifest themselves as states of depression and chronic pain. My research uses both cell systems and animal models to test these hypotheses. Colleagues and I use a combination of imaging techniques to localize cytokine production, bioassays and ELISA (enzyme-linked immunosorbent assays) for pharmacological and functional analyses, electrophysiological (brain slice stimulation) and molecular methods for our studies. In addition to investigating neuron functioning in the brain, trainees in my laboratory also study the peripheral macrophage, a major source of TNF during inflammation. Specifically studying neurotransmitter regulation of TNF production in the periphery is enhancing our knowledge of how the brain controls a peripheral inflammatory lesion. Our studies are designed to investigate the mechanisms of centrally mediated pain as associated with immune dysfunction and to elucidate mechanisms of drugs used to treat such pain states. My projects are evolving to investigate the mechanisms and neural pathways involved in TNF neuromodulator functions during chronic pain (due to peripheral nerve injury and diabetes) and stress-induced depressive behavior. We also study mechanisms contributing to the comorbidity of chronic pain and depression. I collaborate with researchers in several UB departments and at other institutions. Our projects include using noninvasive methods for delivery of anti-TNF therapeutics for chronic pain, elucidating the neural-immune mechanisms involved in the rapid recovery afforded by centrally administered anti-TNF therapy and using nanotechnology-mediated, targeted gene silencing within the CNS. I am invested in helping my undergraduate and graduate students, medical residents and postdoctoral fellows realize their potential and achieve their goals. Previous students have advanced professionally and hold clinical, academic and industrial positions.
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.
Gene Expression; Gene therapy; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Neuropharmacology; Transcription and Translation
The efforts in my lab are broadly directed at the translational research of neuroprotective/neurorestorative agents. Specifically, I am focused on the preclinical and clinical development of therapies used to prevent behavioral and cognitive deficits following traumatic brain injury (TBI) and stroke. Over 800,000 patients each year in the US suffer stroke and more than twice that number suffer TBI. Unfortunately there are currently no FDA approved therapies for TBI. TPA is the only therapy approved for stroke but is only applied in about 4% of stroke patients. Furthermore, while TPA is thrombolytic, it does not limit the cascade of pathology initiated by the original occlusion. We have demonstrated that low dose methamphetamine is highly neuroprotective when administered as an acute treatment (within 12 hours after injury) following severe stroke or TBI. We have show that treatment with methamphetamine significantly improve cognition and functional behavior in rat models of these injuries. This effect is primarily mediated through the activation of a dopamine/PI3K/AKT signaling cascade and results in the preservation of primary neurons, and axons, as well as enhanced granule cell neurogenesis and white mater track remodeling. Furthermore, gene expression analysis suggests methamphetamine treatment significantly reduces pro-inflammatory signals and stabilizes the blood brain barrier. These observations led us to further investigate the potential of low dose methamphetamine to reduce or prevent post-traumatic epilepsy. Using long-term video/EEG monitoring, we determined that methamphetamine treatment significantly reduces the incidence and susceptibility to post traumatic epilepsy/seizures after severe TBI in rats. This becomes quite relevant when one considers that many patients with post-traumatic epilepsy are pharmacoresistant. We are continuing to use the TBI model to investigate the causes of post-traumatic epilepsy and test novel therapeutics. In addition to single severe injury, we are also very interested in the effects of repeated mild TBIs. It has now been observed that multiple mild TBIs can cause clinical seizures in about 50% of rats. Therefore, we are also using this model to investigate the causes of post-traumatic epilepsy and potential therapeutic interventions. We have now completed a phase I human trial of methamphetamine in healthy volunteers and are moving to conduct a phase IIa dose escalation safety study in TBI patients. In addition, we are currently using NGS to examine plasma miRNA changes as potential biomarkers and objective measures of activity to support the phase IIa study. In addition to small molecules, my lab also is investigating the development of Adeno- associated virus (AAV) vector based gene therapy approaches to the treatment of CNS injuries such as post-traumatic epilepsy. Specifically, we are using recombinant AAV vectors to modulate targeted gene expression in a temporal, tissue-specific and cell type-specific manner within the CNS.
Gene therapy; Genomics and proteomics; Immunology; Infectious Disease; Neurobiology; Neuropharmacology; Viral Pathogenesis; Virology
As a postdoctoral fellowship in the Division of Allergy, Immunology & Rheumatology at University at Buffalo I received a NIDA funded National Research Service Award (NRSA) F32 to study the mechanisms of cocaine-induced HIV-1 infection in astrocytes. This was a two year fellowship award ($99,224). I received several Young Investigator Travel Awards to attend and present my research at national conferences including the Society for NeuroImmune Pharmacology, the College on Problems of Drug Dependence and the International Society for NeuroVirology. I was the first to demonstrate that cocaine enhances the replication of HIV in astrocytes, specialized glial cells in the central nervous system. During this time I was first author on 3 publications and contributed as a co-author on 6 publications in internationally recognized, peer reviewed journals including the Journal of Immunology, Brain Research and Biochimica et Biophysica Acta. As a Research Assistant Professor in the Division of Immunology I was funded through a NIDA Mentored Research Scientist Development Award (K01) award to investigate targeted nanoparticles for gene silencing in the context of HIV and drug abuse. This K01, was a five year award, $785000 that allowed for advanced training in nanotechnology and immunology. I applied this new expertise in nanotechnology to the development of innovative methods to control HIV-1 infections, particularly those associated with methamphetamine abuse. I was an invited panel speaker at the International Symposium on NeuroVirology and the American College of Neuropsychopharmacology. During this time, I published approximately 30 peer-reviewed publications in internationally recognized, peer-reviewed journals, including journals such as the Journal of Immunology, Brain Research, and the Journal of Pharmacology Experimental Therapeutics. Six as first author, 1 as senior author and 23 as a co-author. Presently, I am a Associate Professor and Proposal Development Officer in the Department of Medicine at University at Buffalo where I continue to develop my research in drug delivery methods. I am currently investigating exosomes as potential delivery vehicles. Exosomes are one of several types of membrane vesicles known to be secreted by cells including microvesicles, apoptotic bodies, or exosome-like vesicles. Exosomes, unlike synthetic nanoparticles, are released from host cells and have the potential to be novel nanoparticle therapeutic carriers I have recently been invited to be a panel speaker at the American Society of Nanomedicine and the American Society of Gene & Cell Therapy conferences. I have been a principal investigator and co-instigator on NIH funded projects studying multimodal nanoparticles for targeted drug delivery and immunotherapy in Tuberculosis and HIV and a co-investigator on a NYS Empire Clinical Research Investigator Program (ECRIP) to develop a Center for Nanomedicine at UB and Kaleida Health. I have had over eight years of NIH supported funding.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Gene therapy; Genome Integrity; Genomics and proteomics; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Signal Transduction; Stem Cells; Transcription and Translation
The long term mission of our laboratory, which I co-direct with Dr. Ewa Stachowiak, is to understand the principles governing molecular control of neural development, the implications for developmental- and aging-related diseases and the wide ranging effects on brain functions including behavior. The main achievement of our program has been the discovery of “Integrative Nuclear FGFR1 Signaling”, INFS a universal signaling mechanism which plays a novel integral role in cell development and complements other universal mechanisms such as mitotic cycle and pluripotency .Based on these revolutionary findings we have formulated a new theory called “Feed-Forward End-Gate Signaling” that explains how epigenetic factors either extracellular like neurotransmitters, hormonal or growth factors or intracellular signaling pathways control developmental gene programs and cellular development. This discovery is a product of our twenty-year multidisciplinary research that has been reported in several peer-reviewed papers in major journals including Proc. Natl. Acad. of Science (USA), Integrative Biology, Molecular Biology of the Cell, Journal of Cell Biology, Journal of Biological Chemistry, Journal of Physical Chemistry (etc.). In addition, we have applied this theory to analyze the etiology of neurodevelopmental /neurodegenerative disorders, and cancer in order to utilize it in new potential therapies. Towards these goals we have employed new technologies for an in vivo gene transfer, developed new transgenic mouse models for Schizophrenia and Parkinson-like diseases and established an interdisciplinary Molecular and Structural Neurobiology and Gene Therapy Program which has o engaged researchers from the different UB departments, other universities in the US as well as foreign institutions including Hannover Medical School (Germany), Gdansk Medical University, and Polish Academy of Science. Detailed research activities and future goals of our research program: 1. Molecular mechanisms controlling development of neural stem and related cells. In studying molecular mechanisms controlling development of neural stem and related cells we have established a novel universal signal transduction mechanism -Feed-Forward-And Gate network module that effects the differentiation of stem cells and neural progenitor cells. In the center of this module is the new gene-controlling mechanism "Integrative Nuclear Fibroblast Growth Factor Receptor-1 (FGFR1) Signaling" (INFS), which integrates diverse epigenetic signals and controls cell progression through ontogenic stages of proliferation, growth, and differentiation. We have shown that, Fibroblast Growth Factor Receptor-1 (FGFR1) a protein previously thought to be exclusively involved with transmembrane FGF signaling, resides in multiple subcellular compartments and is a multifactorial molecule that interacts with diverse cellular proteins In INFS, newly synthesized FGFR1 is released from the endoplasmic reticulum and translocates to the nucleus. In the nucleus, FGFR1 associates with nuclear matrix-attached centers of RNA transcription, interacts directly with transcriptional coactivators and kinases, activates transcription machinery and stimulates chromatin remodeling conducive of elevated gene activities. Our biophotonic experiments revealed that the gene activation by nuclear FGFR1 involves conversion of the immobile matrix-bound and the fast kinetic nucleoplasmic R1 into a slow kinetic chromatin binding population This conversion occurs through FGFR1’s interaction with the CBP and other nuclear proteins. The studies support a novel general mechanism in which gene activation is governed by FGFR1 protein movement and collisions with other proteins and nuclear structures. The INFS governs expression of developmentally regulated genes and plays a key role in the transition of proliferating neural stem cells into differentiating neurons development of glial cells, and can force neoplastic medulloblastoma and neuroblastoma cells to exit the cell cycle and enter a differentiation pathway and thus provides a new target for anti-cancer therapies. In our in vitro studies we are using different types of stem cells cultures, protein biochemistry, biophotonics analyses of protein mobility and interactions [Fluorescence Recovery after Photobleaching (FRAP), Fluorescence Loss In Photobleaching (FLIP), and Fluorescence Resonance Energy Transfer (FRET)] and diverse transcription systems to further elucidate the molecular circuits that control neural development. 2. Analyses of neural stem cell developmental mechanisms in vivo by direct gene transfer into the mammalian nervous system. An understanding of the mechanisms that control the transition of neural stem/progenitor cells (NS/PC) into functional neurons could potentially be used to recruit endogenously-produced NS/PC for neuronal replacement in a variety of neurological diseases. Using DNA-silica based nanoplexes and viral vectors we have shown that neuronogenesis can be effectively reinstated in the adult brain by genes engineered to target the Integrative Nuclear FGF Receptor-1 Signaling (INFS) pathway. Thus, targeting the INFS in brain stem cells via gene transfers or pharmacological activation may be used to induce selective neuronal differentiation, providing potentially revolutionizing treatment strategies of a broad range of neurological disorders. 3. Studies of brain development and neurodevelopmental diseases using transgenic mouse models. Our laboratory is also interested in the abnormal brain development affecting dopamine and other neurotransmitter neurons and its link to psychiatric diseases, including schizophrenia. Changes in FGF and its receptors FGFR1 have been found in the brains of schizophrenia and bipolar patients suggesting that impaired FGF signaling could underlie abnormal brain development and function associated with these disorders. Furthermore the INFS mechanism, integrates several pathways in which the schizophrenia-linked mutations have been reported. To test this hypothesis we engineered a new transgenic mouse model which results from hypoplastic development of DA neurons induced by a tyrosine kinase-deleted dominant negative mutant FGFR1(TK-) expressed in dopamine neurons. The structure and function of the brain’s DA neurons, serotonin neurons and other neuronal systems including cortical and hippocampal neurons are altered in TK- mice in a manner similar to that reported in patients with schizophrenia. Moreover, TK- mice express behavioral deficits that model schizophrenia-like positive symptoms (impaired sensory gaiting), negative symptoms (e.g. low social motivation), and impaired cognition ameliorated by typical or atypical antipsychotics. Supported by the grants from the pharmaceutical industry we are investigating new potential targets for anti-psychotic therapies using our preclinical FGFR1(TK-) transgenic model. Our future goals include in vivo gene therapy to verify whether neurodevelopmental pathologies may be reversed by targeting endogenous brain stem cells. Together with the other researchers of the SUNY Buffalo we have established Western New York Stem Cells Analysis Center in 2010 which includes Stem Cell Grafting and in vivo Analysis core which I direct. Together with Dr. E. Tzanakakis (UB Bioengineering Department) we have written book “ Stem cells- From Mechanisms to Technologies’ (World Scientific Publishing, 2011). Educational Activities and Teaching: I have participated together with the members of our neuroscience community in developing a new Graduate Program in Neuroscience at the SUNY, Buffalo. I am teaching neuroanatomy courses for dental students (ANA811) and for graduate students (NRS524). At present I participate in team-taught graduate courses in Neuroscience and Developmental Neuroscience (NRS 520, 521 and NRS 524). I am serving as a mentor for several undergraduate, graduate (masters and doctoral students) and postdoctoral fellows in the Neuroscience Program, Anatomy and Cell Biology Program and in the IGERT program in the Departments of Chemistry and Engineering. Additionally to mentoring master and Ph.D. students at the UB, I have helped to train graduate students in the University of Camerino (Italy) and Hannover Medical School (Germany). The works of our graduate students have been described in several publications.
Retina; Gene therapy; Neurodegenerative disorders; Pathophysiology; Protein Folding; Gene Expression; Signal Transduction
I am a Clinician Scientist working in the field of hereditary retinal and macular degenerations. I direct a regional referral service for these diseases at the Ross Eye Institute. My NIH- and VA-funded laboratory is focused on the development of gene-based therapeutics for hereditary retinal degenerations and common age-related macular degeneration.
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.