The University of Texas-Houston (UTH) Medical School and collaborating clinical and basic investigators at the UTH-M.D. Anderson Cancer Center and the UTH-School of Public Health (Human Genetics Center) propose the renewal of the Specialized Center of Research (SCOR) in Scleroderma (systematic sclerosis or SSC) or UTH-SCOR- SSc. The Director of UTH-SCOR-SSc will be Frank C. Arnett, M.D. and the Co-Directors Benoit de Crombrugghe, M.D. (for basic research) and no effective treatment characterized by diffuse cutaneous and visceral fibrosis. The pathogenesis of SSc is unknown, no effective treatment characterized by diffuse cutaneous and visceral fibrosis. The pathogenesis of SSc is unknown, however, there is evidence for both genetic and environmental influences. Thus, the central theme of UTH- SCOR-SSc is the use of molecular approaches to understanding pathogenetic mechanisms, especially genetic factors, and the predictors of outcomes in SSC. Three interacting clinical and basic research project and two cores are proposed, as follows: 1) A human gebine0wide scan for SSc-associated genes using microsatellites (currently in progress) followed by genetic fine mapping using single nucleotide polymorphisms (SNP) in a unique Native American population with high disease prevalence; as well as in a well characterized, multi-ethnic cohort of SSc patients. Also, gene expression profiles in SSc fibroblasts and other tissues will be determined in the context of known metabolism and biochemical pathway using cDNA microarrays in order to better understanding molecular pathogenesis of SSc and to identify candidate genes for disease susceptibility and expression; 2) basic investigations in transgenic murine models of fibrosis, including microarray analyses of fibroblasts to compare with the human studies; 3) a large study of potential demographic, clinical, autoantibody and genetic predictors (including microarrays of SSC fibroblasts and other tissues) of disease outcomes in three ethnic groups (Caucasians, African-Americans and Mexican-Americans); 4) a Tissue Culture Core to process and store fibroblasts from SSC patients for the projects proposed; and 5) an Administrative and Biostatistical Core for administering UTH-SCOR- SSC and providing data management and biostatistical analysis for the projects proposed. The studies proposed here will provide better understanding of both the fundamental pathogenetic mechanisms and potentially useful clinical predictors of outcome in SSc which will lead to more directed therapies and/or disease prevention.
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