The objective of this proposal is to enable the applicant to develop expertise as an independent medical research scientist in the fields of immunology and hematopoiesis.
The specific aims of phase I are the following: 1) To undergo rigorous training within the Graduate School of Microbiology and Immunology, Duke University, to earn a doctoral degree (Ph.D.) in Immunology. 2) To attain laboratory expertise in the areas of hematopoiesis and lymphocyte function and differentiation. Emphasis will be placed on T cell differentiation antigens and clonal analysis of hematopoietic progenitor cells. 3) To utilize these techniques in the study of primitive hematopoietic cells, in an attempt to isolate the lymphohematopoietic stem cell from human bone marrow. 4) To further characterize the cell surface antigen 3A1(CD-7), which was initially defined and characterized by Dr. Haynes, the sponsor of this application. This antigen may be important in the differentiation and commitment of the lymphohematopoietic stem cell. The intensive research experience in phase II will focus upon basic studies of the biology of the bone marrow derived 3A1(+) lymphohematopoietic stem cell isolated in Phase I. Laboratory expertise gained in Phase I will be used to ask specific questions about the regulation of lymphoid vs. non-lymphoid differentiation in this pluripotent cell. Initially, this cell will be characterized by immunophenotypic, functional, histochemical, and morphological methods. Monoclonal antibodies will be raised against this cell and characterized. We will define the growth requirements of this cell (e.g. IL-1, IL-2, IL-3, B-cell stimulating factor (IL-4), thymic and bone marrow stromal cells), so that it can be expanded and cloned in longterm culture. Interactions between the bone marrow derived lymphohematopoietic stem cell and bone marrow stroma, thymic epithelial cells, and other cells of the thymic microenvironment will be explored. This work should make important contributions to the basic study of hematopoiesis. Access to the lymphohematopoietic stem cell also has wide clinical relevance, particularly in the study of the pathogenesis and therapy of aplastic anemia and resistant leukemias. In addition, isolation of the stem cell would allow significant advancement toward understanding the biology of hematopoietic cell maturation, necessary for optimizing autologous and allogenic bone marrow transplantation, as well as gene replacement therapy.
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