Autoimmunity; Immunology; Neurobiology
My research is aimed at understanding the roles of the innate and adaptive immune systems in health and disease. The organs of my interest are the two specialized filtration units, glomeruli and blood-brain barrier, of the kidney and brain respectively. Recently, our understanding of the immune system has undergone a substantial paradigm shift: researchers now recognize that the innate immune system, the body’s first line of defense, assesses the level of danger of a particular event and initiates an adaptive immune response that subsequently confers protection. My studies focus on the role of an important arm of the innate immune system, the complement cascade in inflammatory conditions such as glomerulonephritis and lupus. For both disease conditions, the perfect therapy remains an enigma. Using a gamut of techniques, we are attempting to define the molecular mechanisms involved and the resulting behavioral aberrations. Once molecular targets are identified, therapeutic strategies will be defined. I teach in UB’s Discovery Seminar Program, which is geared for first- and second-year undergraduates. The seminars are taught in a small-class environment to students who share common goals and similar interests, in ways that enhance their academic, civic and personal growth. I teach “The Yin-Yang of Biology” and “Brain: Day and Night,” and I teach as well in UB’s Honors College. I also mentor students through the CLIMB-PRO program. One of my recent students conducted research that resulted in a publication in the journal Kidney International.
Rheumatology; Immunology; Autoimmunity
My research revolves around IL-14 and its role in immunological memory. Studies delve into 3 areas - vaccination, autoimmunity and lymphoid malignancies. The majority of my current work involves studies examining early events in Sjogren‘s syndrome. We have identified new autoantibodies that occur early in the course of the disease. We are examining mediators involved in the early injury to the salivary and lacrimal glands. We are studying events that result in the transition from the autoimmune disease to lymphoma.
My research focus is on the study of the interaction of inflammatory leukocytes and fibroblasts with tumor cells in human lung and ovarian tumor microenvironments by using an immunodeficient tumor xenograft model. This model includes the tumor, the tumor-associated stromal fibroblasts and the inflammatory cells, including lymphocytes. In my lab, I work with a research team of students and postdoctoral fellows to study the immune response of cancer patients to their tumors. Our data indicate that tumor-specific lymphocytes, once present in the tumor microenvironment, become hyporesponsive and fail to attack and kill tumor cells. This hyporesponsiveness is due to an arrest or checkpoint in the T cell receptor (TCR) signaling machinery. Our studies are designed to gain a better understanding of the molecular events that are responsible for signaling arrest. We also aim to determine ways to prevent, or even reverse the TCR signaling arrest, for example, by eliminating or blocking the lipid-mediated disruption of the TCR signaling cascade. Using the tumor xenograft models, we have structurally identified the immunoinhibitory factors present within the tumor ascites fluids and determined the mechanism by which they arrest the TCR signaling. We found that these cells fail to respond to activation signals due to the disruption of the TCR signaling cascade that occurs at, or just proximal to the activation of PLC-γ. An identical TCR signaling arrest also occurs in human T cells found in chronic inflammatory tissues. Using the xenograft models, we established that a local and sustained release of IL-12 into the tumor microenvironment activates the quiescent tumor-associated T cells to produce and secrete IFN-γ, which mobilizes an immune-mediated eradication of the tumor. We recently found that lipids present within the ascites fluids of human ovarian tumor mediate a reversible arrest in the TCR signaling pathway of ovarian tumor-associated T cells. We have now determined that extracellular microvesicles (exosomes) isolated from human ovarian tumors and tumor ascites induce a rapid and reversible arrest in the T cell signaling cascade. The T cell inhibition is causally linked to phosphatidylserine that is expressed on the outer leaflet of the exosome membrane. The target of this arrest is diacylglycerol, and the induced suppression is blocked or reversed by diacylglycerol kinase inhibitors. This suggests a likely mechanism by which the tumor-associated exosomes arrest both CD4+ and CD8+ T cell activation. The ability to eliminate or block/reverse that inhibitory activity of the exosomes represents a potentially viable therapeutic target for enhancing patients’ antitumor response and for preventing the loss of function of CAR-T cells upon entry into the tumor microenviroment. These findings will provide valuable information in designing new immunotherapeutic strategies for patients with advanced cancer.
Immunology; Infectious Disease
My patient care and teaching responsibilities are centered at the Veterans Administration hospital where I care for hospitalized patients and maintain an active outpatient clinic. I enjoy teaching medical students and residents in both lecture and small group settings. In addition, my laboratory is open to interested undergraduate, graduate and medical students and residents seeking to gain a research experience. Research interests of my laboratory focus on two key areas of the function of specialized immune cells called macrophages. Our first area of interest concentrates on the immunologic roles of mammalian macrophage gangliosides. Gangliosides are unique molecules that hold diverse regulatory roles as receptors and as mediators of cell differentiation in cells of most species. Our studies encompass ganglioside regulation of macrophage inflammatory responses, ganglioside-associated alterations of the architecture of macrophage cell membranes in HIV-infected individuals, and the function of macrophage gangliosides as receptors for bacterial pathogens and toxins. This work will lead to a better understanding of mechanisms of macrophage activation, to permit manipulation of host immune responses. Our second area of interest centers on the regulation of inflammatory responses of human alveolar macrophages by respiratory bacterial pathogens and bacterial antigens that contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Studies encompass defining the repertoire of inflammatory mediators of human alveolar and blood-derived macrophages regulated by bacterial pathogens and characterizing bacteria-regulated immunologic properties of macrophages, in patients with COPD. These investigations into fundamental mechanisms of dysfunctional immune responses of macrophages underlying the progression of COPD are providing the basis for designing novel and more effective therapies.
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.
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.
Autoimmunity; Bioinformatics; Genomics and proteomics; Immunology; Infectious Disease; Molecular and Cellular Biology; Molecular genetics; Neurobiology
My primary research is in the field of biomedical ontology development. An ontology is a controlled, structured vocabulary intended to represent knowledge within a particular domain. Terms in an ontology have logical relationships to each other and to terms in other ontologies, to allow for reasoning and inference across the ontology. Biomedical ontologies allow annotation and integration of scientific data within particular fields of science and medicine, and their careful curation and logical structure facilitate data analysis. My work in biomedical ontology is strongly informed by my earlier experience in laboratory research in immunology, genetics, molecular biology and virology. My research group works on ontologies for both basic and clinical applications, in collaboration with researchers both at UB and other institutions. I led efforts to revise and extend the Cell Ontology, which is intended to represent in vivo cell types from across biology. We worked extensively to bring it up to community-accepted standards in ontology development, placing particular emphasis on improving the representation of hematopoietic cells and neurons. We are developing the Cell Ontology as a metadata standard for annotation and analysis of experimental data in immunology in support of the National Institute of Allergy and Infectious Diseases (NIAID) ImmPort Immunology Database and Analysis Portal and Human Immunology Project Consortium. We have also developed ways to use the Cell Ontology in support of the analysis of gene expression data linked to cell types and have contributed to the Functional Annotation of the Mammalian Genome (FANTOM) 5 Consortium‘s work on identifying gene transcription start sites across multiple cell types and tissues. My research team is also developing the Neurological Disease Ontology to represent clinical and basic aspects of neurological diseases in order to support translational research in this area. In collaboration with clinical colleagues at UB, we are initially focusing on Alzheimer’s disease and dementia, multiple sclerosis and stroke. We have as well developed a companion ontology, the Neuropsychological Testing Ontology, to aid in the annotation and analysis of neuropsychological testing results used as part of the diagnosis of Alzheimer‘s disease and other neurological diseases. I am a long-term member of the Gene Ontology (GO) Consortium and have a particular interest in the representation of immunology and neuroscience in the GO. I am also involved in UB’s contribution to the Protein Ontology and contribute as well to the work of the Infectious Disease Ontology Consortium, Immunology Ontology Consortium and Vaccine Ontology Consortium. I teach and mentor students at the master’s and doctoral levels, and advise undergraduate, graduate, and medical students in summer research projects as well.
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.
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.
Gene Expression; Immunology; Molecular and Cellular Biology; Molecular genetics; Signal Transduction
I am the administrator for flow cytometry in the Confocal Microscopy and Flow Cytometry Core Facility that serves investigators throughout the university. In that role, I oversee the use of the LSRFortessa and the FACSCalibur analytical flow cytometers, providing instruction on their use and the analysis of acquired data and serving as a consultant on the design and interpretation of experiments. I also operate the FACSAria cell sorter, providing sterile live cell sorting. In addition, I operate and provide assistance to users on the application of cytometric bead array analysis on the FACSArray, as well as Elispot analysis using the Zeiss KS-ELISPOT microscope. My own research centers on investigating the responsiveness of human T cells in the tumor microenvironment of lung and ovarian cancer and lymphomas. In that research, I am a coinvestigator in a collaborative group of oncologists and immunologists coordinated by Richard Bankert, PhD. We have observed that T cells in the tumor microenvironment are hyporesponsive to T cell receptor-mediated activation and that factor(s) present in ovarian tumors and associated ascites fluid can cause this hyporesponsiveness. We are investigating the mechanism(s) of this phenomenon. Also, as an approach to the in vivo study of the immune response to human tumor associated antigens, our group has established a novel xenograft model by injecting human tumor cell aggregates of solid ovarian tumor biopsies intraperitoneally into immune-deficient NSG mice. The result is a human tumor microenvironment in the greater omentum of the mice, i.e., the omental tumor xenograft (OTX) model. The progression of the human tumor xenograft closely approximates the characteristics of the tumor in cancer patients, and it is possible to quantify the presence of tumor cells and stromal cells in the OTX model. These findings have led to our program goals to: 1.) determine whether the OTX model can be used as a predictive tool of the outcome of therapeutic approaches for the treatment of human ovarian cancer and B cell lymphoma, and 2.) determine whether the inhibition of activation in the tumor microenvironment can be reversed so that the antitumor T cell response can be reactivated.
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.
Pulmonary & Critical Care Medicine; Immunology; Protein Function and Structure; Proteins and metalloenzymes
I am engaged in clinical, teaching and research responsibilities related to the evaluation and treatment of patients with pulmonary disease or patients who are critically ill. My inpatient practice situated at the medical intensive care unit (MICU) at the Buffalo General Medical Center (BGMC) positions me to provide ongoing medical care to patients who are critically ill and require significant life support therapies to sustain life or vital bodily functioning. I am specifically interested in asthma, COPD, interstitial lung disease, pleural disease, pulmonary hypertension and lung cancer, but deal with a variety of lung disease. I evaluate patients with pulmonary disorders including shortness of breath, lung masses, abnormal chest imaging, abnormal pulmonary function tests, chronic obstructive pulmonary disease (COPD), asthma, pleural disease, interstitial lung disease, pulmonary hypertension, and lung cancer, at the UBMD practice location at Conventus. As a member of the UBMD pulmonary division, I provide inpatient pulmonary consultation at both BGMC and Roswell Park Cancer Institute. Currently, I am focusing on the analysis of Big Data in the medical/healthcare fields. I am mainly focused on the application of drug repurposing in translation and clinic research. Additionally, I am engaged in the study of the human airways microbiome and metagenome. The human microbiome is the collection of all the microbial organisms in a human body, and the corresponding metagenome is the collection of the genes, and gene products of the microbes. Due to the potential impact of the microbiome on human health and disease, I am interested in studying the putative effects the interaction with human hosts, specifically innate immunity interaction with the metagenome in lung disease. My collaborators include the Division of Allergy and Immunology. We endeavor to elucidate immune cell function in airway diseases such as asthma and COPD. Our research focuses on the development of therapeutics aimed at novel targets identified as necessary in the molecular basis of pulmonary disease; efficacious laboratory results will generate more effective treatment plans for patients. I am actively involved in teaching medical students, residents, and fellows about the appropriate care of the patient with either pulmonary disease and critical illness.
Apoptosis and cell death; Cell growth, differentiation and development; Cytoskeleton and cell motility; Immunology; Signal Transduction; Stem Cells
My independent research at The University at Buffalo focuses on targeting the mammary gland microenvironment by evaluating cellular and tissue responses during specific developmental windows of mammary gland remodeling including puberty, the period of hormonal withdrawal during estrous cycling, or post-lactational involution. My choice to focus on discrete times of development for chemopreventive intervention, rather than long-term (and often life-time) intervention, represents a unique approach of short-term exposure at critical points of mammary gland development. Our goal is to allow women to bypass the need for lifelong compliance to a chemopreventive diet or drug regimen in order to attain lifelong protection against breast cancer. Developmentally targeted dietary interventions being investigated in our lab include continuous administration of oral contraceptives, dietary exposure to conjugated linoleic acid, and ethanol.
Anesthesiology; Cardiovascular Disease; Cardiopulmonary physiology; Immunology
Special interest in academic medicine and active research in the kinetics of inflammatory responses in acute lung injury and myocardial ischemia reperfusion.
Pulmonary & Critical Care Medicine; Immunology; Membrane Transport (Ion Transport)
My clinical responsibilities include working as one of five Intensive Care Unit physicians at the Buffalo VA Medical Center (Buffalo VAMC). I also have a pulmonary medicine outpatient clinic at the UBMD multispecialty practice in Williamsville. My outpatient clinic accepts all patients, with a focus on interstitial lung disease (associated with collagen vascular disorders such as systemic lupus erythematousus [SLE]), scleroderma, rheumatoid arthritis, Sarcoidosis, the idiopathic pulmonary pneumonitis syndromes (IPF/UIP) and advanced chronic obstructive pulmonary disease (COPD). We are one of the founding sites of the Greater New York Sarcoidosis Consortium and work closely with our neurology colleagues in managing patients with respiratory complications of neuromuscular disorders such as ALS, Duchenne‘s Muscular Dystrophy and others. I focus my research on understanding the impaired immune response to infection that occurs in patients with COPD. This impaired immune response leads to more frequent disease exacerbations and more rapid disease progression. My lab has optimized a noninvasive macrophage model (monocyte-derived macrophage) to study how to restore the immune function of alveolar macrophages in patients with COPD. Using this model, we study cell surface receptor expression, cytokine responses and intracellular signaling using flow cytometry, bead arrays and molecular biology techniques. My research team collaborates with Dr. Sanjay Sethi and other researchers in the areas of pulmonary, sleep medicine, critical care, infectious disease and microbiology. Undergraduates, medical students, residents and fellows are welcome in my lab. I am committed to teaching the next generation of physicians. I teach medical students in years two through four; in addition, I teach the residents and the pulmonary and critical care medicine fellowship trainees who rotate with me on the inpatient and outpatient services. I also teach the internal medicine and anesthesia residents and provide grand rounds lectures for the Buffalo VAMC, Buffalo General Medical Center and Erie County Medical Center. I serve on the Resident Clinical Competency Committee and as a formal resident advisor, shepherding my mentees through residency and helping them launch their professional careers. My door is always open to any trainee at any level.
I am a physician board-certified in internal medicine and medical oncology. I care exclusively for adult patients diagnosed with acute leukemias, myelodysplastic syndromes, chronic myeloid leukemia, chronic myeloproliferative disorders and other bone marrow disorders. I care for people diagnosed with these illnesses who are hospitalized at Roswell Park Cancer Institute or who come to the leukemia service at Roswell Park for outpatient care. I have an active translational research program. My research interest is focused on understanding more about the role of the immune microenvironment in facilitating persistent disease in acute myeloid leukemia. My goal is also to develop novel immunotherapeutic strategies for this disease. I invite interested students to my lab to collaborate with me in conducting research. I am responsible for supervising, teaching and mentoring medical students, internal medicine residents and hematology/oncology fellows at Roswell Park. I lecture to the hematology/oncology fellows as part of their curriculum and to residents rotating on the leukemia service. My focus during these lectures is mainly myeloid malignancies. I also teach and train at the bedside with the fellows, residents and students who are on service with me, and I teach and train in clinic settings as well. Given my expertise, I am able to provide trainees with comprehensive knowledge about how to render the best possible care for individuals diagnosed with bone marrow disorders, a medically complex patient population.
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.
Dermatology; Immunology; Neurobiology
As a physician with clinical expertise in dermatology and a bench scientist with over 15 years of experience in cutaneous immunology, my research focuses on autoimmune disorders and neuroimmunology of the skin. I am particularly interested in the blistering autoimmune skin disease Pemphigus vulgaris (PV), which, while rare, serves as an excellent model to investigate the basic aspects of autoimmune disease in general. The work in our laboratory is patient-based, and we have an unparalleled collection of blood samples and clinical information from over 200 individuals affected by PV enrolled in our IRB-approved studies focusing on mechanisms of autoimmunity (T effector and regulatory cells, immunoglobulin subtypes, auto-antigen and auto-antibody profiles) as well as clinical expression of disease. We have also recently applied cutting-edge atomic force microscopy technology to the investigation of antibody effects in the tissue level in PV. Another main interest of mine is investigating the role of stress hormones and neural transmitters in skin diseases, in particular the effect of adrenaline on Langerhans cells (resident dendritic cells within the epidermis). It has long been postulated that stress can affect certain skin conditions, but only recent experimental evidence has established a role of the neuroendocrine system in cutaneous inflammation. Exploring the role of stress hormones and neural transmitters promises to affect greatly the way we view and treat many skin diseases including, but not limited to atopic dermatitis and psoriasis. As a research assistant professor in the department of dermatology I oversee the work of postdoctoral fellows, MD/PhD students and medical students involved in the day-to-day operations of our basic science laboratory. I also actively participate in dermatology resident teaching through regularly scheduled basic science journal clubs and by supervising resident research rotations in the laboratory.
Cardiology; Cardiovascular Disease; Internal Medicine; Radiology; Cardiopulmonary physiology; Autoimmunity; Cardiac pharmacology; Gene Expression; Immunology; Stem Cells
I am a cardiologist with specialized training in advanced cardiac imaging. I see outpatients at the Heart and Lung Center of Buffalo General Medicine Center (BGMC), and I care for inpatients through the cardiology consult and inpatient services at BGMC. As an advanced imaging cardiologist, I am responsible for developing and advancing the cardiac computed tomography (CT) and magnetic resonance imaging (MRI) programs at the Gates Vascular Institute (GVI) and providing these services to patients. These advanced, noninvasive imaging techniques allow physicians to perform in-depth, 3-D evaluation of the coronary tree, myocardium, heart valves, pericardium and great vessels. These imaging tools allow for the best possible diagnoses and care of patients. My research spans basic science, translational and clinical fields and combines the cross-discipline expertise on magnetic resonance (MR) technology with molecular biology. My overall goal is to study the consequences of ischemia-induced myocardial injury, with a focus on their therapeutic reversal. My research laboratory at UB’s Clinical and Translational Research Center (CTRC) is devoted to the development of novel time-and-tissue-targeted MRI methods for integrative understanding of cardiovascular pathophysiology in preclinical models. We have several interesting research projects, e.g., we have recently discovered that the presence of high-risk plaques in the carotid arteries predict future incidence of myocardial infarction and stroke. The results emphasize that the nature of atherosclerosis and the use of comprehensive non-invasive computed tomography angiography (CTA) will help identify patients who are at higher risk of developing ischemic stroke. These research results will help physicians employ early therapeutic strategies for these high-risk patients. I mentor medical students, residents and fellows both in clinical and research settings, and I precept cardiology fellows at the Heart and Lung Center at BGMC. In addition, I am deeply engaged in furthering the research and clinical education of our house staff. Our trainees have published their research in highly esteemed peer-reviewed journals, and many have routinely presented their work at national and international scientific conferences. I am committed to facilitating the career goals of my mentees while I continue to advance my own career as a clinician, researcher and mentor.
Immunology; Infectious Disease
The focus of my laboratory is to understand regulatory mechanisms during infection and autoimmunity at mucosal sites, particularly within the gastrointestinal tract. The adult human intestine alone contains up to 100 trillion micro-organisms─and no other tissue is submitted to a greater level of antigenic pressure than the gut, which is constantly exposed to food and environmental antigens and the threat of invasion by pathogens. At birth, for example, the human gastrointestinal tract undergoes a massive exposure to these antigens, and throughout the average human life there are multiple instances of the remodeling of the gut flora following infection. All these occurrences impose a unique challenge to the gastrointestinal environment. In response, to maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. Several subsets of immune cells with immune modulatory function reside within the gastrointestinal tract. Specifically, we study Foxp3 expressing regulatory T cells (Tregs), which play a central role in controlling intestinal homeostasis. Recent studies have demonstrated that the ability of Tregs to control defined polarized settings requires plasticity, the acquisition of characteristics specific to the glycoprotein CD4+ T effector subsets. Such adaptation comes with an inherent cost, however; as my research team and other researchers have demonstrated, in extreme instances of inflammation such adaptation can actually be associated with the expression of pro-inflammatory effector cytokines (i.e., interferon gamma and interleukin 17A). We recently identified GATA3, the canonical Th2 transcription factor, as a critical regulator of Treg adaptation during inflammation in tissues. Our goal is to understand how GATA3 regulates this and to identify other factors involved in Treg adaptation during inflammation. Our laboratory employs natural enteric parasitic infections of mice and the T cell dependent model of colitis to decipher both the environmental cues and cell- intrinsic requirements for Treg cell plasticity, stability and function at mucosal sites. The ultimate goal of our research is to clarify the pathogenesis of inflammatory bowel disease (IBD) and develop novel treatment modalities for patients.