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, which can be changed by injury or disease, affects how cells proliferate and migrate. My research is in blood vessels, particularly in arterial stiffening, which is a significant risk factor for the progression of cardiovascular disease- the 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, my lab 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 for the development of drugs to counteract their function. The goal of my research is to contribute new fundamental knowledge about arterial stiffness, which will 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.
Eukaryotic Pathogenesis; Immunology; Infectious Disease; Microbial Pathogenesis; Microbiology; Molecular Basis of Disease; Signal Transduction; Vision science
Toxoplasma gondii is an obligate intracellular parasite that has the unique ability of infecting most nucleated cells in almost all warm-blooded animals. It is one of the most widespread infections in the world: approximately 50 percent of the world‘s population is infected. Luckily, most infected people are asymptomatic; however, in AIDS patients and other immune-compromised individuals, Toxoplasma causes serious and life-threatening disease. Besides its own medical importance, we study Toxoplasma because it represents an ideal model system to study how other related pathogens cause disease. These include Plasmodium, which is the causative agent of malaria that is responsible for millions of deaths worldwide, and Cryptosporidium, which causes another important secondary infection in AIDS patients. Toxoplasma is a great model system because it can easily be grown in vitro, its genome has been sequenced and it can be genetically manipulated. My research team and I are focused on two different but related questions. First, we want to know how the parasite grows inside of its host cell. One of the important things Toxoplasma must do to grow is hijack host cell pathway and factors. We are using functional genomic assays such as microarrays and genome-wide RNA interference (RNAi) screens to identify these host factors. Identifying them is important because if the parasite cannot use these pathways, the parasite will not grow or cause disease. Thus, these pathways represent novel drug targets. As an example, we discovered that oxygen-regulated transcription factors in the host cell are necessary to support parasite growth. We are currently identifying how these transcription factors function and how the parasite adapts to the various oxygen environments it encounters during its lifecycle. Second, we want to know how Toxoplasma affects the central nervous system and how anti-Toxoplasma immune responses function in the central nervous system. These questions are important because Toxoplasma primarily causes disease in the brain and retina. Our work has revealed that when Toxoplasma actively grows in the brain (a condition known as toxoplasmic encephalitis), it causes a massive reorganization of inhibitory synapses. These changes inhibit GABAergic synaptic transmission and this inhibition is a major factor in the onset of seizures in infected individuals. A second line of research using an ocular infection model has focused on defining how immune responses in the central nervous system are generated by Toxoplasma and then resolved once the infection is under control.
Endocrinology, Diabetes and Metabolism; Neurodegenerative disorders; Pathophysiology; Endocrinology; Molecular Basis of Disease
Dr. Browne’s research is focused primarily on the clinical biochemistry of oxidative stress (OS) in human health and disease. Specifically, his research focuses on mechanisms of oxidative lipid damage and the antioxidant roles of high-density lipoproteins (HDL. This research includes pure biomarker method development and validation employing primarily high pressure liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) along with collaborative clinical studies of the role of oxidative stress in cancer, infertility and women’s health, and neurological disease. Current studies on-going in Dr. Browne’s laboratory include investigations of the role of HDL and PON1 in embryo morphology outcomes during in vitro fertilization (IVF), a study of the role of oxysterols in Multiple Sclerosis disease progression and investigations of the role of bioactive lipid mediators in response to air pollution.
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.
Internal Medicine; Nephrology; Bioinformatics; Molecular Basis of Disease; Cardiac pharmacology
I have a passion for challenge and an allergy to routine. This has driven my interest for research and clinical medicine, mainly internal medicine. I am currently a nephrologist at UBMD and a Faculty at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences. In my clinical practice, I manage all aspects of kidney disease, renal replacement therapies including dialytic therapies and kidney transplant, hypertension, as well as disorders of fluid and electrolytes. With my group, I also provide nephrology consultations at the Roswell Park Cancer Institute. I particularly favor this part of my clinical activity, considering the very specific and challenging nephrological problems arising in cancer patients. I have a passion for education and never say no for opportunities to teach or learn. At the expense of longer days, I always take opportunities to teach fellows, residents and students. I strongly believe in problem-based learning, in the sense that what is learned is best remembered as a solution to a problem. So far, my research has focused on cardiovascular disease, mainly cardiac and vascular mechanics. In this phase of my career in nephrology, I am moving towards issues interfacing the cardiovascular system and the kidneys.
Allergy and Immunology; Medical Microbiology; Infectious Disease; Microbiology; Genomics and proteomics; Immunology; Microbial Pathogenesis; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Gene Expression; Signal Transduction; Protein Function and Structure; Bacterial Pathogenesis
Research efforts in my laboratory are focused in the fields of immunology and bacterial pathogenesis, two diverse fields of biomedical research for which I have two separate research groups. Projects in both fields are performed by undergraduates, doctoral and master’s degree students, postdoctoral fellows and senior research associates. One major focus of my laboratory is studying the regulation of mucosal immune responses. We investigate the cellular and molecular events by which Type II heat-labile enterotoxins (HLTs), produced by certain strains of Escherichia coli, modulate immune responses. We have demonstrated that LT-Ilia, LT-IIb and LT-IIc, when co-administered with an antigen, have the capacity to enhance antibody and cellular immune responses to that antigen. Using a variety of immunological and cellular technologies, including flow cytometry, fluorescence resonance energy transfer (FRET) detection, cytokine multiplex analysis, mutagenesis, quantitative Reverse Transcription PCR (qRT-PCR), RNA-sequencing (RNA-Seq) and a variety of transgenic mice, we are investigating the mechanisms by which these immunomodulators productively interact with various immunocompetent cells (T cells, B cells, dendritic cells, macrophages) to induce or suppress cytokine production, costimulatory ligand expression and cellular proliferation. A practical outgrowth of these experiments is the potential to engineer novel recombinant vaccines by genetically fusing antigens from different pathogens to the enterotoxins. Recent experiments have shown that these HLT are lethal for triple-negative breast cancer cells, which has opened a new area of oncological research for the lab. A second focus of my laboratory is to investigate the molecular mechanisms by which adherent-invasive Escherichia coli (AIEC) induce, exacerbate or prolong the symptoms of inflammatory bowel disease (IBD) and Crohn’s disease, two acute and chronic inflammatory diseases of the human gut. In vitro, AIEC strains invade into the cytoplasm of several epithelial cell lines. Using recombinant screening methods and RNA-Seq technologies, we are identifying the genes of AIEC that are required to attach and to invade gut cells.
Oncology; Cell Cycle; Cell growth, differentiation and development; Gene Expression; Molecular Basis of Disease; Molecular and Cellular Biology; Signal Transduction; Transcription and Translation
Protein phosphorylation is an essential mechanism by which intercellular signals regulate specific intracellular events. Protein kinases, the enzymes catalyzing protein phosphorylation reactions, represent a major superfamily of genes, collectively representing 2% of the protein coding potential of the human genome. Current projects in Dr. Edelman‘s lab are devoted to the role of protein kinases in prostate and ovarian cancer. These projects utilize a wide range of techniques and involve, collaboration with investigators at Roswell Park Cancer Institute to develop protein kinase-targeted therapies for both types of cancer.
Neurology; Cytoskeleton and cell motility; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Signal Transduction; Inherited Metabolic Disorders; Transgenic organisms
My laboratory seeks to understand the molecular basis of myelination and myelin diseases. Myelin is a multi-lamellar sheath that invests large axons and permits rapid conduction of nerve signals. Failure in myelin synthesis and myelin breakdown cause several important neurological diseases, including multiple sclerosis, leukodystrophies and peripheral dysmyelinating neuropathies. In some of these diseases, genetic mutations cause defects in cytoskeletal, adhesion and signaling molecules. I work with a team of undergraduate and graduate students, postdoctoral fellows, technicians, senior scientists and many international collaborators to discover how these molecules normally coordinate cell-cell and cell-extracellular matrix interactions to generate the cytoarchitecture of myelinated axons. We use a variety of approaches, including generation of mice carrying genetic abnormalities, cultures of myelinating glia and neurons, imaging, biochemistry and morphology to understand the role of these molecules in normal and pathological development. By comparing normal myelination to the abnormalities occurring in human diseases, we aim to identify molecular mechanisms that pharmacological intervention might correct. For example, we described how the protein dystroglycan associates with different proteins, some of which impact human neuropathies, depending on a proteolitic cleavage that can be regulated to improve the disease. Similarly, we found that molecules such as integrins and RhoGTPAses are required for glia to extend large processes that will become myelin around axons. In certain neuromuscular disorders, defective signaling pathways that converge on these molecules cause failure to produce or mantain an healthy myelin Finally, in collaborations with scientists and clinicians in the Hunter J. Kelly Research Institute, we are generating transgenic forms of GalC, an enzyme deficient in Krabbe leukodystrophy, to investigate which cells requires the enzyme. Investigating how GalC is handled may help find a cure for this devastating 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.
Bioinformatics; Genomics and proteomics; Immunology; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Gene Expression
The current focus of my lab is on iron metabolism in animals and humans. From the practical viewpoint, iron is an important nutrient, but its ability to act in the ferrous and ferric state also makes it toxic. Thus, iron deficiency is the most frequent disorder in the world and hereditary hemochromatosis (HH) is the most common Mendelian disorder in the United States. Our research is related to erythroid differentiation on the fundamental level and to genetic and acquired diseases on the applied level, with four long-term themes: 1.) analysis of the molecular basis of differential gene expression among tissues and during development, with hemoglobin synthesis and red blood cell (RBC) development as models; 2.) application of molecular and genetic advances to inherited diseases; 3.) iron metabolism; 4.) study of gene variation in populations and divergence of gene loci during evolution. New vistas have opened recently for the anemia of chronic diseases, leading us to re-exam how microbes and their human hosts fight for iron. We approach these issues by working on rodent models like the Belgrade rat, plus a series of genetically engineered mice. The rat has a hypochromic, microcytic anemia inherited as an autosomal recessive. The defect is in an iron transporter called DMT1 (or slc11a2, previously called Nramp2 or DCT1) that is responsible for iron uptake by enterocytes and is also responsible for iron exiting endosomes in the transferrin cycle. The rats appear to have a severe iron deficiency, and although dietary iron and iron injection increase the number of RBCs, they do not restore the RBCs nor the rat itself to a normal phenotype. Recent discoveries show that DMT1 is ubiquitous and responsible for transport of other metals such as Mn and Ni. It occurs in the kidney, brain and lung at even higher levels than in the GI tract or in erythroid cells. It also has multiple isoforms, and we have cloned them and developed cell lines that express high levels of particular isoforms. We have specific antibodies to the isoforms and assays for each of the mRNAs too. Future projects in my lab will continue to address whether DMT1 is dysregulated in HH. We will also tackle how DMT1 functions in neurons, pneumocytes and other tissues, look at isoforms of DMT1 under circumstances where we suspect that they must have different functions from one another, and examine DMT1’s relevance to iron metabolism and human disease. Because we cloned the gene and identified the mutation, a number of molecular and cellular approaches can now be used. As evidence indicates that metal ion homeostasis fails in Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, research on DMT1 has opened new vistas for these disorders.
Pediatric Surgery; Pediatric Urology; Pulmonary Disease; Surgery; Surgical Critical Care - Surgery; Thoracic Surgery; Surgery - Trauma; Surgery - Laparoscopic; Prenatal Diagnosis; Fetal Surgery; Miniature Access Surgery; Cell growth, differentiation and development; Molecular Basis of Disease
-To be a recognized leader in academic pediatric surgery (clinical surgery, clinical/basic science research, teaching and administration), -To build a state of the art surgical department, divisions, and programs congruent withthe mission goals, and needs of institutions (university, hospital, other departments), patients and their families and faculty (full time and volunteer) -To create the requiste environment for students, residents, and faculty to optimize career development -To maintain a busy clinical pratice of open and miniature access surgery for fetuses, infants, children -To cross train students (MD, RN, DDS, Phar D.,MPH, Basic Science, Residents and Fellows(all specialties), Faculty (all Health Science Schools),and Community Healthcare Professionals in the requisite MBA Skill Sets, Entrepreneurism, and Big Data analysis to optimize their professional development, careers and their patients‘ outcomes in this complicated and ever changing Healthcare environment -To be actively involved in teaching and practicing Interprofessional Care (IPC) and Interprofessional Education (IPE) -To continue to train and mentor academic gerneral surgeons -To continue to train and mentor academic pediatric surgeons -To continue to teach and mentor students at various levels -To continue laboratory and clinical incestifations in the following areas: lung development, congenital diaphragmatic hernia, fetal physiology, birth defects, prenatal diagnosis of surgical problems, fetal surgery, the genetic aspects of surgical disease, fetal frowth factors, the physiology miniature access surgery, surgical robotics, ECMO, trauma, the education process for students, residents, and fellows virtual reality, surgical simulation, telelmedicine, telesurgery, teleconferencing, telementoring, and computer applications in medicein -To continue research and development with corporate biomedical parners -To continue to advocate for children and children‘s health care
Bioinformatics; Cell growth, differentiation and development; Genomics and proteomics; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Gene Expression; Stem Cells; Transgenic organisms
My research goal is to gain a better understanding of how proteins that interact with DNA regulate RNA transcription, DNA replication and metazoan development. I mentor undergraduate and graduate students in my lab; we focus on the structure and function of the Nuclear Factor I (NFI) family of site-specific DNA binding proteins, and we are investigating their roles in development. Our work has been made possible by our development of loss-of-function mutations of the NFI genes in the mouse and C. elegans. We are addressing four major questions in my laboratory and in collaboration with a number of talented collaborators: What is the structure of the NFI DNA-binding domain? How does NFI recognize and interact with DNA? Does NFI change the structure of DNA when it binds? What proteins interact with NFI to stimulate RNA transcription and/or DNA replication? These research questions are explored in my lab through two major projects focused on the role of NFIB in lung development and the role of NFIX in brain development. When NFIB is deleted from the germline of mice the animals die at birth because their lungs fail to mature normally. This provides a good model for the problems that occur with premature infants, whose lungs also fail to mature normally. We are using this model to determine how NFIB promotes lung maturation with the goal of being able to stimulate this process in premature infants. In our NFIX knockout animals, the brains of the animals are actually larger than normal and contain large numbers of cells in an area known to be the site of postnatal neurogenesis. We have evidence that NFIX may regulate the proliferation and differentiation of neural stem cells, which produce new neurons throughout adult life. Our aim is to understand the specific target genes that NFIX regulates in the adult brain to control this process of neurogenesis.
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.
Cardiovascular Disease; Cytoskeleton and cell motility; Molecular Basis of Disease; Molecular and Cellular Biology
My primary research interest is the behavior of endothelial cells, which form the inner lining of blood vessels and are key players in the remodeling events that occur during wound healing, aneurysm formation, tumor growth, and a wide variety of disease conditions. There are two questions about endothelial behavior that drive most of the research in my laboratory: (1) How does an endothelial cell migrate during wound healing and blood-vessel remodeling? We are particularly interested in the motor protein, myosin II, and how it exerts force within the cytoskeleton to push or pull the cell as it moves. In order to study the organization and movements of cytoskeletal proteins - and not just there biochemical properties - we use a variety of light microscopic methods to examine the dynamics and biochemistry of cytoskeletal proteins in living migrating endothelial cells. We also use conventional biochemical, genetic, and pharmacological manipulations to investigate the regulatory events that control myosin II behavior in situ. (2) How do endothelial cells sense and respond to their mechanical environment? Blood vessels remodel to accommodate long-term changes in blood flow. Certain flow environments can cause destructive remodeling that leads to cerebral aneurysms (local “ballooning” of vessels). Working with biomedical engineers in the laboratory of Dr. Hui Meng at the Toshiba Stroke Research Center, we use cell culture and whole animal systems to examine how endothelial cells respond to specific hemodynamic micro-environments in order to understand the mechanism and regulation of flow-induced remodeling, especially as it relates to cerebral aneurysms. A third interest is understanding the response of cultured endothelial cells to electrical fields, which have been shown to orient endothelial migration in vitro and to suppress edema in vivo by enhancing the endothelial permeability barrier.
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.
Cardiology; Cardiovascular Disease; Internal Medicine; Molecular Basis of Disease
I am a board-certified cardiologist trained in multimodality cardiovascular imaging. I have completed the most advanced training possible in echocardiography and nuclear cardiology, and I am also certified to perform and interpret cardiac computed tomography (CT) and adult and congenital cardiac magnetic resonance imaging (MRI). I supervise and interpret these studies at the Buffalo General Medical Center (BGMC) and the Gates Vascular Institute (GVI). As a clinical cardiologist, I care for patients in the BGMC coronary care unit and the cardiac step-down unit. I provide consultative services at BGMC as well. I also leverage my background in epidemiology and public health to advise appropriate utilization of imaging at BGMC and the GVI for patients with known or suspected ischemic heart disease. I use my training to educate providers about the best way to determine the likelihood of ischemic heart disease in their patients and how they can improve the application of these tests to diagnose patients, determine their prognoses and institute appropriate therapies. As a clinical investigator, my research is geared toward imaging arrhythmogenesis in patients with heart failure. The goal of my research is to use imaging-based approaches to guide cardiac device therapies in heart failure patients. This includes implantation of defibrillators and biventricular pacemakers. I use nuclear cardiology-based imaging approaches to assess dyssynchronous cardiac contraction and sympathetic denervation in patients with heart failure to guide whether a particular device should be implanted or not. Once a decision is made to implant a device, these imaging approaches can also guide how the device should be implanted. My research helps identify the patients who will benefit from devices as treatment modalities, since these devices are invasive and expensive. My research also helps identify patients who will not benefit, which protects patients from a needlessly invasive and costly procedure. As a faculty member in the Division of Cardiovascular Medicine, I teach my team of fellows, residents and students during and after rounds when I am on consult and inpatient services. I also supervise the fellows’ clinic at BGMC.
Inherited Metabolic Disorders; Membrane Transport (Ion Transport); Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; Transgenic organisms; Vision science
Most physiological processes and numerous disease states influence or are influenced by pH. Even relatively small deviations in whole body pH can have devastating consequences for our health. Our bodies are subject to a constant challenge from dietary and metabolic acids, thus it is critical for the body to have mechanisms that tightly regulate pH. Blood plasma pH is maintained at a value close to 7.4, predominantly thanks to the buffering action of 24 mM bicarbonate (HCO3-). HCO3- neutralizes acid, generating carbon dioxide and water (HCO3- + H+ to CO2 + H2O), preventing lethal acidosis. I study the SLC4 family of membrane proteins that move acid/base equivalents across cell membranes. Notable members include  the Na/2HCO3 cotransporter NBCe1-A that reclaims HCO3- from filtered blood plasma in kidney tubules (preventing loss of vital plasma HCO3- to the urine),  NBCe1-B that promotes fluid removal from the corneal stroma (preventing corneal edema and vision loss),  the Cl-HCO3 exchanger AE1 that promotes O2-CO2 exchange in red blood cells, and  SLC4A11 that conducts H+ and promotes corneal clarity. Dysfunction of SLC4 family members is associated with renal tubular acidosis, blindness, cancer, deafness, epilepsy, and hypertension.
Gene Expression; Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; Transcription and Translation
Our laboratory utilizes combined genetic, biochemical and molecular biological approaches to investigate the molecular mechanisms involved in the initiation and regulation of eukaryotic transcription. Previous work in our laboratory utilizing both the budding yeast Saccharomyces cerevisiae and human cells resulted in the identification and biochemical characterization of mutants of nuclear RNA polymerase II (RNAPII) and the general transcription factors TFIIB and TFIIF that coordinately affect transcription start site utilization and transcript elongation. These studies supported a model where yeast and human TFIIF induce global conformational changes in RNAPII that result in structural and functional changes in the polymerase active center. Our current studies are focused on elucidating the mechanisms of kinetoplast transcription by the mitochondrial RNA polymerase of Trypanosoma brucei. T. brucei is a protozoan parasite that is the causative agent of African sleeping sickness (trypanosomiasis) in humans and nagana in animals. Procyclic trypanosomes growing in the midgut of the tsetse fly have a fully functional mitochondrion whereas trypanosomes in the mammalian bloodstream exhibit repressed mitochondrial function. The mitochondrial DNA in trypanosomes is unusual in its structure, comprising a highly catenated network of maxicircles and minicircles termed kinetoplast DNA (kDNA). Surprisingly, very little is known about the cis-acting elements and the trans-acting factors governing the transcription of maxicircles and minicircles. Our objective is to elucidate the mechanisms and regulation of T. brucei kDNA transcription with the ultimate goal of developing therapeutic agents.
Neurodegenerative disorders; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Signal Transduction; Protein Function and Structure; Neuropharmacology
I focus my research on the activation mechanisms of fast neurotransmitter receptors. We seek to define the activation pathway, modulatory mechanisms and structure-function relationships of the N-methyl-D-aspartate (NMDA) receptor to better understand the roles played by this protein in the brain. NMDA receptors are the most abundant glutamate-stimulated, Ca2+-conducting ion channels in brain and spinal cord. They are the predominant molecular devices for controlling synaptic development and plasticity and govern memory and learning processes. Understanding the mechanisms that control their activity may lead to more effective strategies to treat neuropathies including stroke, neurodegenerative conditions, chronic pain and addiction as well as mental disorders such as schizophrenia and epilepsy.
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.
Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Molecular and Cellular Biology; Protein Folding; Protein Function and Structure; Signal Transduction
Work in my lab seeks to elucidate the transduction mechanisms of ion channels involved in thermal sensation and pain, such as the heat-activated vanilloid receptors (TRPV1-4) and the cold-activated TRPM8 – the so-called thermal TRP channels. Expressed in peripheral afferent nerve endings, these channels function as an array of thermometers for sensing ambient temperature from noxious cold to noxious hot. While all proteins are thermally sensitive, thermal TRP channels are gated by temperature and possess unprecedentedly high temperature dependence. But the mechanisms of their temperature gating has remained mysterious, in contrast to our abundant knowledge on other types of ion channel gating (e.g. voltage or ligand-driven). Thermal TRP channels are also distinct for their polymodal responsiveness. TRPV1, for example, is responsive to heat, voltage, pH, capsaicin (i.e. the hot ingredient of chili peppers) among many other irritant compounds. The channels are thus informative for deciphering how biological proteins achieve multitasking. Thermal TRP channels also have receptor-like roles in mediating intracellular signaling. The calcium influx through the channels has potentially a broad spectrum of functional consequences, one of which is the desensitization of the channels themselves, a phenomenon that is believed to underlie peripheral analgesics. Our research is centered on problems like these, and we approach them by a combination of techniques such as recombinant mutagenesis, patch-clamp recording, fluorescence measurements, quantitative modeling, etc, which together allow us to draw insights into functions of the channels at mechanistic levels. Complementing our experimental studies, we are also interested in development of methodology to ever extend experimental resolutions. For example, to time-resolve temperature-dependent activation of thermal TRP channels, we have developed a laser diode-based temperature clamp apparatus, which achieves for the first time a submillisecond resolution (>105 oC/s) while capable of clamping temperature constant. For the past decade we have also been developing sophisticated algorithms for statistical analysis of single-molecule measurements such as single-channel patch-clamp recordings, which can help unravel the richness of data pertaining to molecular mechanisms at high resolutions. Together, these approaches provide us with unique abilities for in-depth studies of structure-mechanisms of ion channels.
Cardiopulmonary physiology; Cytoskeleton and cell motility; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Molecular Basis of Disease; Signal Transduction
My research interests center on mechanical and electrical biophysics, from molecules to organs, and the development of new tools. And, in recent years I worked in transitional science; bringing basic science to the clinic and to industry. My basic research interests are on cell mechanics and the mechanisms by which mechanical forces are transduced into messages such as voltage and chemicals such as ATP and Ca2+. I discovered mechanosensitive ion channels in 1983. My methodology has included patch clamp, high resolution bright field light microscopy, low light fluorescence microscopy, high speed digital imaging, TIRF, digital image analysis, high voltage EM with tomography, Atomic Force Microscopy, molecular biology, natural product and recombinant protein biochemistry, NMR and microfabrication and microfluidics. We discovered the only known specific inhibitor of mechanosensitive ion channels and uncovered its remarkable mode action by using a combination of electrophysiology and chiral chemistry. We have demonstrated potential clinical applications of the peptide for cardiac arrhythmias, oncology, muscular dystrophy, and incontinence. We have developed many scientific tools. Recently we developed a sensor chip to measure cell volume in real time, and that is now entering production with Reichert Instruments of Buffalo. We also have an Small Business Innovation Research contract to develop a microfluidic, bipolar, temperature jump chip with ALA Scientific and developed a microfabricated Atomic Force Microscopy probe that is an order of magnitude faster and more stable than any commercial probes. We have made probe operable with two independent degrees of freedom on a standard Atomic Force Microscopy. This permits us to remove all drift and coherent noise by using one axis to measure the substrate position and the other the sample position. These probes are being produced by a new company in Buffalo, kBtwist. We have used the Atomic Force Microscope combined with electrophysiology to study the dynamics of single voltage dependent ion channels. This technique provides a resolution of >0.01nm in a kHz bandwidth. I have developed other hardware including the first automated microelectrode puller, a micron sized thermometer and heater and a high speed pressure servo. Some of these devices have been patented by the University of Buffalo and some are in current production. To analyze the reaction kinetics of single molecules, we developed and made publicly available (www.qub.buffalo.edu) a complete software package for Windows that does data acquisition and Markov likelihood analysis. The development was funded by the National Science Foundation, National Institutes of Health and Keck over the last fifteen years, and has been applied to ion channels, molecular motors and the even the sleep patterns of mice. We have taught at UB hands-on course to use the software, and the course was attended by an international group of academic scientists and students, government and industry.
Behavioral pharmacology; Cardiac pharmacology; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Neurobiology; Neuropharmacology; Signal Transduction; Transgenic organisms
With over 400 genes coding for them in humans, ion channels play a significant role in most physiological functions. Drug-induced channel dysfunction often leads to a variety of disorders and results in significant incidence of serious injury and death. We investigate molecular mechanisms underlying neurodegenerative disorders and cardiac arrhythmias induced by ion channel dysfunction arising from genetic factors and/or drug interactions. The tools used for these investigations include genetic, electrophysiologic, pharmacologic, molecular and cell culturing methods. Preparations used for experiments include Drosophila as a genetic model system, and human cell lines expressing human ion channels that play an important role in critical-to-life functions including cardiac rhythm, respiration and the central nervous system.
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.
Cell growth, differentiation and development; Microbiology; Molecular Basis of Disease; Molecular and Cellular Biology; Regulation of metabolism; Signal Transduction; Toxicology and Xenobiotics; Vitamins and Trace Nutrient
Dr. Willsky’s research focuses on the role of oxovanadium compounds in cellular metabolism. V is a trace metal believed to be required for growth. Oral administration of oxovanadium compounds alleviates the symptoms of Diabetes in animal models and humans. The techniques of genetics, microbiology, molecular biology, biochemistry, pharmacology, magnetic resonance spectroscopy, and cell physiology are used. The diabetes-altered gene expression of genes involved in lipid metabolism, oxidative stress and signal transduction is returned to normal by V treatment of rats with STZ-induced diabetes, as demonstrated using DNA microarrays. Inhibition of tyrosine protein phosphatases is believed to be a major cause of the insulin-like effects of V. Our results implicate the interaction of V with cellular oxidation-reduction reactions as being important in the anti-diabetic mechanism of V complexes. A new project in the lab studies the mode of action of medicinal plant mixtures used by the native healers of Peru.
Neurodegenerative disorders; Pathophysiology; Cytoskeleton and cell motility; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Neuropharmacology; Signal Transduction
Synaptic Mechanisms of Mental Health and Disorders Our research goal is to understand the synaptic action of various neuromodulators that are linked to mental health and illness, including dopamine, stress hormones, and disease susceptibility genes. Specifically, we try to understand how these neuromodulators regulate glutamatergic and GABAergic transmission in prefrontal cortex (PFC), which is important for emotional and cognitive control under normal conditions. We also try to understand how the aberrant action of neuromodulators under pathological conditions leads to dysregulation of synaptic transmission in PFC, which is commonly implicated in brain disorders. The major techniques used in our studies include: • whole-cell patch-clamp recordings of synaptic currents, • viral-based in vivo gene transfer, • biochemical and immunocytochemical detection of synaptic proteins, • molecular analysis of genetic and epigenetic alterations, • chemogenetic manipulation of neuronal circuits, • behavioral assays. By integrating the multidisciplinary approaches, we have been investigating the unique and convergent actions of neuromodulators on postsynaptic glutamate and GABAA receptors, and their contributions to the pathogenesis of a variety of mental disorders, including ADHD, autism, schizophrenia, depression, PTSD and Alzheimer's disease.
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.