GENE REGULATION IN LYMPHOHEMATOPOIETIC STROMAL CELLS

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This proposal is based on the premise that a common, multi-potent progenitor cell gives rise to the adipocytes, osteoblasts, and lympho- hematopoietic supporting cells of the bone marrow microenvironment. It is designed to test a number of inter-related hypotheses concerning the regulation of bone marrow stromal cell differentiation and function in vitro and in vivo. Four SPECIFIC AIMS focus directly on these issues: (1) To determine whether monoclonal antibodies directed against a cloned stromal cell line can be used to define distinct subpopulations within primary derived stromal cells by flow cytometry. (2) To see whether distinct cytokine gene "superfamilies" regulate stromal cell function in a common manner. (3) To compare the lymphohematopoietic function of morphologically distinct stromal cell sub populations in vitro. (4) To determine the in vivo kinetics of cytokine expression relative to stromal cell differentiation following hematologic stress or osteogenic induction. These studies will examine the inter-dependence of stromal cell adipogenesis, osteogenesis, and lympho-hematopoiesis and determine if these functions are mutually exclusive. Ultimately, the goal of this project is to develop a comprehensive model describing the cytokine mechanisms which determine bone marrow stromal cell physiology. These findings will have direct application to disease states reflecting stromal cell dysregulation, including myelofibrosis, osteoporosis, and secondary bone metastases by osteolytic or osteosclerotic tumors. In addition, they may address questions relating to stromal cell homeostasis in other tissues. As clinicians expand their use of cytokines in the treatment of lymphothematopoietic disorders, improved understanding of the stromal cell response to these agents will become of increasing importance.