Faculty active in this area of research are listed below. For a brief description of their research interests, click on their name in the list. Clicking on the name at the beginning of the brief description links to their detailed personal website.
Scott R. Barnum, PhD My research interests have been on the production and regulation of several components in the complement system. These interests focused on the central nervous system (CNS) based on growing evidence for a role for complement in CNS diseases. This led us to examine for the production and cytokine-mediated regulation of additional activation components, as well as, complement regulatory proteins. It is now clear that, at least in vitro, most if not all complement proteins can be synthesized by astrocytes, microglia, and to our surprise, neurons. Since these initial observations, we have moved into in vivo models systems. Using a variety of disease models, including bacterial meningitis, brain trauma, experimental allergic encephalomyelitis (EAE) and a murine stroke model, we have demonstrated that a number of complement proteins and receptors are widely produced in the intact CNS under pathological conditions. We have recently expanded our interest in complement in the CNS to include C-reactive protein (CRP) and beta2-integrins and several of their ligands. We are examining the role of these molecules in EAE using several complement and adhesion molecule knock-out mice. In addition, we are using mice transgenic for CRP and several transgenic mouse lines that express either the complement regulatory protein (sCrry) or the complement anaphylatoxins, C3a or C5a, only in the CNS under the control of an astrocyte-specific promoter. Our data suggest that targeting these molecules has therapeutic value. In other studies, we are examining the role of gamma/delta T cells in autoimmune disease in the CNS with a particular interest in trafficking and activation mechanisms. We have recently shown that these cells are critical to the development of EAE, but surprisingly little is known about the function of these cells in the pathogenesis of demyelinating disease.
Khurram Bashir, MD Clinical, epidemiological and outcomes research in immunologic disorders of the central nervous system, specifically multiple sclerosis
Etty (Tika) Benveniste, PhD Dr. Benveniste's research is directed toward understanding how the immune system and central nervous system (CNS) communicate with each other. Specifically, her laboratory is studying the occurrence of shared cytokines/chemokines between cells of the immune and nervous systems. Astrocytes and microglia, the major glial cells of the CNS, have been shown to act as antigen-presenting cells in the CNS. We are examining the mechanisms by which cytokines modulate class II major histocompatibility complex (MHC), matrix metalloproteinases (MMPs) and CD40 proteins on these cells, the regulation of mRNA expression for class II MHC, MMPs and CD40, and the transcription factors involved in gene expression. The ability of astrocytes and microglia to secrete several immunoregulatory molecules (tumor necrosis factor, interleukin-6, macrophage chemotactic protein, interleukin-8) is also being studied, with an emphasis on the biological stimuli that induce these cytokines/chemokines, intracellular signaling events involved in the response, and the molecular mechanisms of gene regulation. We have also initiated studies to examine the role of MMPs in astroglioma migration and invasion, and how interferons inhibit this response at the transcriptional level. These projects will provide a better understanding of how bidirectional communication occurs between the immune and nervous systems, and how these interactions affect the functionality of glial cells. These studies are also relevant to understanding the pathogenesis of several neurologic diseases such as multiple sclerosis, an autoimmune disease of the CNS, and HIV-1 Associated Dementia.
Suresh B. Boppana, MD Dr. Boppana’s laboratory is studying the pathogenesis of congenital cytomegalovirus (CMV) infections. Congenital CMV infection is the most frequent congenital infection and a leading cause of brain damage and sensorineural hearing loss in children. The focus of the work in our laboratory include: 1. Understanding the intrauterine transmission of CMV in women who were CMV seropositive before pregnancy. We recently showed that acquisition of a new CMV strain is associated with intrauterine transmission and damaging congenital infection in immune mothers. Our ongoing studies will attempt to define the role of maternal reinfection, maternal strain-specific immune responses and other factors in transplacental transmission and damaging congenital infections in infants born to immune mothers; 2. Definition of the mechanisms of hearing loss, in particular, the development of late onset and/or progressive hearing loss in children with congenital CMV infection. We are investigating the role of virus burden and characterizing the virus specific cellular immune responses in congenitally infected children to better delineate the pathogenesis of hearing loss in children with congenital CMV infection; 3. Understanding the virologic and immunologic characteristics of primary CMV infection.
G. Yancey Gillespie, PhD The main thrust of Dr. Gillespie's research is to develop and test specific therapies for treatment of malignant brain tumors in adults and children. One current focus is construction of replication conditional herpes simplex viruses that are both oncolytic for glioma cells and express foreign therapeutic genes. Gene transfer includes both pro-drug converting enzymes and cytokines under different promoter systems. Pro-drug enzyme systems currently being studied are cytosine deaminase (CD) alone or as a fusion protein with uracil phosphoribosyl transferase (UPRT) and purine nucleoside phosphorylase (PNP). A second focus involves studies with the CD and CDUPRT systems in both replication incompetent adenovirus and conditionally replication competent adenovirus. Adenoviruses targeted to cell surface receptors on glioma cells are being constructed to provide tumor specificity. Cytokines expressed from replication competent HSV that are being studied include TNFa, IL-2, IL-4, IL-5, IL-10, IL12, IL-16. These systems are validated by in vitro assays first before being advanced to safety and efficacy assessment in a variety of murine models of intracranial malignant gliomas. These models include transplantable intracranial gliomas of human origin (in immunocompromised scid or nude mice) or mouse origin (in syngeneic conventional mice). Dr. Gillespie's group also has acquired 2 transgenic glioma mouse models and use high-field strength (8.5T) magnetic resonance imaging to detect and monitor tumor growth in transgenic mice. One intriguing observation is the fact that many of these viral oncolytic and transgene therapies are markedly enhanced by modest doses of whole brain irradiation. This phenomenon is being studied at the cellular and molecular levels to determine how it can be best employed as a therapeutic strategy. Vectors that are to be advanced to clinical trials are tested for neurotoxicity in non-human primates. Finally, small peptides that exert an anti-angiogenic effect on tumor neovasculature or that induce apoptosis in human glioma cells are being studied as therapeutic agents in vitro and in animal models of malignant brain tumors.
Kent Keyser, PhD Dr. Keyser's research interests center on acetylcholine (Ach) and Ach receptors. Acetylcholine is used as a transmitter in many portions of the vertebrate nervous system and much information is available concerning the cells that contain it and its synthesis and release mechanisms. However, until recently little was known about Ach receptors and the neurons that express them, During the past several years various groups have 1) purified the ligand-binding (a) and structural (b) subunits of neuronal nicotinic acetylcholine receptors (nAChRs), 2) cloned their cDNAs, and 3) raised antibodies against them. These studies have revealed that there are at least 11 different subunits which, in various combinations, can theoretically yield a vast number of nAChR subtypes, each characterized by a unique subunit composition. Many of the subtypes that have been described to date differ from one another in their pharmacological characteristics. Therefore, the effects of Ach or its agonists depends upon which receptor subtype is present at a given synapse. Acetylcholine is known to act as a transmitter in the retina and affects the response properties of many ganglion cells, including those that display directional selectivity. My research program involves the investigation of the normal pattern of expression of nAChRs in the retina and central visual structures during embryogenesis and in the adult animal. Another aspect of the research involves the detection of additional receptor subunits/subtypes and the determination of what receptor subunits are found together within individual receptor complexes. Among his long term goals are studies of the factors that regulate expression of different Ach receptor subtypes in various areas of the nervous system.
Jianmei Wu Leavenworth, MD, PhD Dr. Leavenworth's main research interest is to understand the mechanisms of self-tolerance, focusing on molecular and cellular elements that regulate effector and regulatory cell subsets of the immune response. Her long-term goal is to seek effective strategies for cancer immunotherapy using mouse models and specimens from patients with malignant tumors, including gliomas.
Chander Raman, PhD Dr. Raman’s research interrogates molecular and cellular mechanisms driving the immunopathogenesis of autoimmune diseases with a special emphasis on multiple sclerosis (MS) and rheumatoid arthritis (RA). Within this context, the research interest of the Raman laboratory is the study of activation and differentiation of effector T cells and B cells in the pathogenesis of these autoimmune disease. Current investigations involve human samples from patients with MS or RA as well mouse models to study these diseases. The major areas of investigation are:
- The mechanisms modulating the activation of T-cells and differentiation to pathogenic (Th1, Th17 and ThIFNγIL-17 –dual producers), regulatory (nTreg, iTreg) Th subsets and cells of the innate immune system (dendritic cells, macrophages and microglia). Within this area of study, the Raman laboratory has a special interest in type 1 and type 2 interferons, and TGFβ family proteins in the pathogenesis of MS, RA and the mouse model, experimental autoimmune encephalomyelitis (EAE)
- Molecular mechanisms by which CK2 and GSK3 modulates effector and regulatory cells in the pathogenesis of autoimmunity
- Role of CD5 in T cell and B-1a B cell development, differentiation, immunity and pathogenesis – the laboratory focuses on B-1a B cell-dependent T-independent antibody responses, T-dependent antibody responses, autoreactive B-cell generation and persistence and regulatory B-cells. For these studies, the Raman laboratory has generated unique knock-in CD5 mutant mice in which signaling domains associated with CD5-inhibitory activity (ITIM) and CD5-CK2 activation have been ablated
- TGFβR3/betaglycan dependent regulation of adaptive immune effector cells in the pathogenesis of autoimmune diseases
Douglas A. Weigent, PhDThe primary aim of my research program in immunoendocrinology is to establish the biological significance of growth hormone (GH) and growth hormone releasing hormone (GHRH) production in the immune system. The major objectives of the present research are the following: (1) to determine the factors governing the production of lymphocyte GH and GHRH by studying the activity of luciferase reporter gene constructs in lymphocytes; (2) to determine the differences or similarities in the GH and GHRH mRNA in lymphocytes versus pituitary cells; (3) to identify the GH and GHRH producer cells; (4) to determine the autocrine /paracrine effects of lymphocyte GH and GHRH on cytokine synthesis, antibody synthesis and apoptosis in the immune system; (5) to determine whether lymphocytes have a GHRH receptor; and (6) to determine whether GH and GHRH are produced during invasion of the host by viruses , bacteria, or tumors, and whether this same substance can restore deficiencies in immune deficient animals. The results of these studies will increase our understanding of immunophysiology and establish the role of GH and GHRH in the commonality between the neuroendocrine and immune system.