IMMUNOREGULATORY FUNCTIONS OF THE ISOFORMS OF CD44

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The objective of this proposal is to enable the applicant to develop expertise as an independent medical research scientist in the fields of basic immunology and autoimmunemediated connective tissue disease. The applicant proposes to accomplish this objective in two phases over a five year period. Phase l will be devoted primarily to didactic learning and the acquisition of laboratory skills necessary to carry out the research proposed in phase Il. The specific aims of phase I are the following: A. To undergo rigorous training within the Graduate School in the Dept. of lmmunology, Duke University, to earn a doctoral degree (Ph.D.) in lmmunology. In order to attain this goal, the applicant will begin graduate school in Sept. 1993 and has selected coursework that will be accomplished during this phase. B. To attain laboratory expertise in the area of lymphocyte and monocyte function, especially with regards to the role that these cells play in the abnormal immune response of diseases such as rheumatoid arthritis. In order to attain this goal, work will be carried out on the transmembrane proteoglycan CD44. CD44 and its ligand hyaluronan (HA) are involved in leukocyte cell surface interactions that modulate the immune response. Differential expression of the various isoforms of CD44 on leukocytes and production of a soluble form of CD44 likely lead to the ability of CD44 to modulate CD3-T cell receptor mediated T lymphocyte activation and to regulate cell surface binding of HA to leukocytes. The specific aims of this part of phase l are: 1. To characterize the CD44 Isoforms present on human peripheral blood T lymphocytes, B lymphocytes and monocytes especially with regards to the molecular characteristics that allow binding of HA to CD44. 2. Characterize monoclonal and polyclonal antibody reagents that bind to specific isoforms and/or functional epitopes of CD44 molecules. The intensive research experience in phase II will utilize the reagents and knowledge gained about the role of the different CD44 isoforms in T lymphocyte activation and their ability to bind HA to study the regulation of CD44 expression and to study what role CD44 plays in the pathogenesis of rheumatoid arthritis. The specific aims of phase II are: 1. To define the extracellular signals and the intracellular molecular events that regulate CD44 binding to HA and enhance TCR-mediated T cell activation. 2. To define the regulatory role of CD44 in the immune response and determine the immune-mediated functions of the individual CD44 isoforms. 3. Examine the abnormal immune response in rheumatoid arthritis utilizing the antibody reagents developed in phase land the knowledge gained about the regulation of CD44.