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Inflammation/ Atherosclerosis | |
Immunology | |
Cancer |
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Neurosciences | |
Aging | |
Genetics |
Research Area: The role of cell surface carbohydrates
in T cell development and function Research Interests: Cell surface glycosylation
is a complex and tightly regulated process, yet little is known
about the
function of saccharides on cell surface glycoproteins and glycolipids.
Our laboratory is studying the role of cell surface saccharides
on T lymphocytes. We have found that a carbohydrate binding protein
termed galectin-1 binds to glycoproteins on T cells, and, at precise
stages during T cell development and activation, induces the T cells
to undergo apoptosis, or programmed cell death. We are characterizing
the mechanism of cell death induced by galectin-1, and determining
what makes a T cell susceptible to apoptosis via this pathway, using
a variety of biochemical, molecular biology, cell biology Research Area: Pathogenetic mechanisms in HIV infection and inflammatory bowel disease Research Interests: Our group is devoted to identifying genetic traits and their functional cellular counterparts in immune function. This basic immunologic question is being addressed in the context of two diseases. First, our lab is engaged in the search for candidate microbial pathogens in inflammatory bowel disease. This search involves the use of disease specific marker antibodies for the detection of cognate microorganisms; and, representational display analysis, to identify candidate pathogens on the basis of marker genes expressed at lesional sites. Second, we are tackling the identity of host traits conferring susceptibility to HIV-1 pathogenesis. This work addresses role of viral gene products on function of infected host cells, and the mechanistic relationship of host immunodeficiency in B cell lymphomagenesis. Research Interests: Clinical areas of responsibility in the division of laboratory medicine include chemistry, toxicology and immunochemistry. My research interests involve three areas of investigation: 1) Characterizing human follicular dendritic cell immunobiology and the role of follicular dendritic cells in regulating T cell responses in germinal centers; 2) Defining the role of germinal centers in the production of IgE allergic responses; and 3) Developing dendritic cell-based vaccines capable of generating in vivo anti-tumor cell responses to control minimal residual disease following conventional therapies. Research Area: Immune dysfunction associated with aging and chronic infection. Research Interests: Our research is focused on the immune deficiency of aging and AIDS, with particular emphasis on a novel aspect of T cell biology known as replicative senescence. Replicative senescence describes the irreversible state of growth arrest which all normal human somatic cells reach after a finite number of cell divisions. In addition to the cell cycle arrest, senescent cells show a variety of changes in gene expression and function. We have defined certain characteristics of replicative senescence in human T lymphocytes in cell culture, and have then shown that T cells with these identical characteristics accumulate in the elderly as well as in younger persons infected with HIV. Current studies are focused on defining the pleiotropic effects of senescent CD8 T cells on other aspects of immune function and on bone homeostasis, as well as on testing gene therapy approaches to reverse replicative senescence. I have recently been named to the Elizabeth and Thomas Plott Endowed Chair in Gerontology, and I teach one of the year-long Freshman GE Cluster courses entitled: Frontiers of Human Aging. Finally, I am Director of the Human Tissue-Research Center Shared Resource Core of the Jonsson Comprehensive Cancer Center, which serves as a centralized unit within the Dept of Pathology and Laboratory Medicine to coordinate the procurement, processing, quality control, and distribution of human tissue samples for research purposes. Research Area: Antimicrobial Peptides in Host Defense and Inflammation Research Interests: Multicellular organisms, including humans, employ potent and rapidly acting antimicrobial defense mechanisms that are mediated by small peptide antibiotics. Unlike conventional antibiotics produced by specialized metabolic pathways of bacteria and fungi, the antibiotics of higher eukaryotes are generated by posttranslational processing of gene-encoded prepropeptides. The microbicidal granules of phagocytic cells and the secretions on mucosal surfaces are particularly rich in such peptides. Our research is focussed on two large families of mammalian antibiotics: defensins and "cathelin-related" peptides. We are studying: 1) their structure, activity and distribution in cells and tissues, 2) the functions of propeptides in biosynthesis and subcellular targeting, 3) the regulation of antibiotic peptide biosynthesis by developmental, tissue-specific and microbial signals, and 4) the roles of antibiotic peptides in host defense and inflammation. Experimental approaches range from analysis of gene regulation in cell lines and transgenic mice, recombinant production and antimicrobial testing of natural and modified peptides, to histopathologic studies and assays of samples from human patients and experimental animals. Potential applications include the development of novel antibiotic medications and the production of transgenic animals with increased disease resistance.
Research Area: Cell differentiation in the immune and hematopoietic systems Research Interests: The aim of work in my laboratory is to define microenvironmental and systemic signals that regulate the development of B and T cells from immature hematopoietic precursors. Much of our work has focused on primary B cell production and has resulted in the identification of bone marrow stromal cell and endocrine derived factors that control growth and differentiation within the B cell developmental pathway. Additional studies are focusing on the regulation of early T cell development by the thymic microenvironment. A long-term, thymic epithelial cell dependent culture system that maintains CD4-CD8- intrathymic progenitors with normal developmental potential has recently been developed and is being used to characterize immature thymocytes and to identify factors that affect early thymopoiesis. Research Area: Immunity at Mucosal Surfaces Research Interests: The ability of the immune system to protect mucosal surfaces against invasion by pathogens is a poorly understood process. Mucosal surfaces are continually exposed to the outside environment but unlike the skin, have other functions such as adsorbing nutrients, exchanging gases or supporting reproduction. However, if an immune response proceeds unchecked, chronic inflammation develops which leads to pathologic reactions and disrupted tissue function. The focus of our lab is to understand how host immune responses are induced and regulated within mucosal sites. As a model system we study infections caused by the obligate intracellular bacteria Chlamydia trachomatis. Chlamydial organisms dwell in mucosal epithelial cells and often persist despite the production of immunity. Chronic chlamydial infections are an important cause of pelvic inflammatory disease, ectopic pregnancy, and infertility in women and have also been linked with arthritis and atherosclerosis. Dendritic cells and Th1 CD4 T cells that produce IFN-gamma are important for developing protective immunity against Chlamydia infections and our studies are focused on these cell types. Specifically, we are investigating how the route of immunization (mucosal vs. parenteral) influences the development of a protective immune response, the role of dendritic cells in protective immunity and whether T-regulatory CD4 cells are important for controlling or interfering with Th1 responses against Chlamydia. Our overall goal is to contribute to the production of a protective vaccine and/or therapeutic intervention against tissue pathology induced by chronic infections. Research Area: Epigenetics and signal transduction mechanisms in B-cell development and neoplasia. Research Interests: Our group studies the basic biological mechanisms involved in B lymphocyte development and neoplasia utilizing AIDS-related lymphoma (AL) as a model system. AL occurs in 5-7 million HIV-infected individuals worldwide. These tumors are high-grade B-cell malignancies that arise in the unique setting of severe immunodeficiency, chronic antigenic stimulation and altered patterns of cytokine production. These unusual features strongly suggest that novel transforming genes and mechanisms function in AL formation. This hypothesis is supported by the extensive surveys of known oncogenes, tumor suppressor genes and candidate tumorigenic herpesviruses, such as EBV and HHV-8, which have not revealed a consistent link between individual AL lesions. A subtraction-based gene discovery program, combined with high-throughput candidate gene screening, has resulted in over 200 AL-specific genes being identified, 65 of which are unique and thus far uncharacterized. Early studies of one gene, TCL1, suggests that it functions to promote cell survival and proliferation by interacting with the AKTcell signaling pathway. TCL1 is normally down-regulated during B-cell differentiation; however, in both AL and non-AL, TCL1 levels remain aberrantly high suggesting a role in promoting mature B-cell lymphomas . TCL1 transgenic mice have been generated that develop lymphoma, establishing a model system to study the normal and abnormal biochemical and signaling functions of TCL1. Further characterization of this model indicates that it is one of the first to accurately model the vast majority of B- cell cancers that arise in humans, which has been a major goal in hematology/oncology research for many years. Deciphering the molecular mechanisms that contribute to the development of AIDS-related and non-AIDS B-cell cancer in the context of normal B lymphocyte differentiation is complex and requires a multifaceted approach. Major current themes in the lab include understanding how TCL1 dysregulation contributes to lymphomagenesis, characterization of additional differentially-expressed genes in B-cell lymphomas and new investigations of novel epigenetic mechanisms controlling gene expression in health and disease. Recently, in studies linked to TCL1 gene regulation, we have discovered a novel type of DNA methylation that appears to have a role in chromatin structure and gene expression. Methylation of the internal cytosine in CC(A/T)GG motifs causes gene silencing. Major questions we are currently addressing include identification of the methyltransferase and associated proteins involved in this new epigenetic regulation and its significance in B lymphocyte development and neoplasia. Wagar,
Elizabeth A. M.D. |
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