The long term goal of this multidisciplinary project is to identify abnormal regulatory characteristics of fibroblasts and smooth muscle cells (SMC) cultured from fibrotic lesions in order to elucidate the pathogenesis of fibroproliferative disorders, and to use genetic approaches to identify genes that predispose to these conditions, particularly in persons of African descent. Characteristics to be studied in cultured cells are those reported to be abnormally regulated in fibroproliferative conditions, i.e., keloids and rheumatoid arthritis. Responses to be examined are cell growth and synthesis of matrix proteins, specifically, collagen, elastin, and fibronectin. Effectors to be studied include hydrocortisone, transforming growth factor beta, interleukin-1, prostaglandins and phorbol esters. General hypotheses to be tested are: (I) a defect in a regulatory mechanism that controls growth and matrix synthesis accounts for the fibroproliferative characteristics of cells from fibrotic lesions, e.g., keloid fibroblasts, gingival fibroblasts from chronic periodontitis, atherosclerotic SMC, and uterine fibroma SMC; and (2) mutations in specific genes predispose to fibroproliferative disorders in persons of African descent.
Specific aims are: 1. determine whether cells from fibrotic lesions differ from normal cells in regulation of growth and matrix synthesis by the above effectors; 2. characterize the mechanisms of these differences by determining the step(s) on the signal transduction pathway involved in misregulation and the step on the gene expression pathway at which misregulation occurs; 3. use position cloning techniques to identify genes responsible for keloids and hypertension.
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