COLLAGEN GENE REGULATION IN DEVELOPMENT AND DISEASE

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DESCRIPTION: (Adapted from the applicant's abstract) - Type I collagen, the most abundant protein in vertebrates, has diverse biologic function, including providing tensile strength to connective tissues, forming the framework of connective tissue in all major internal organs, and promoting cell migration and differentiation during development. Thus, a detailed (but still lacking) knowledge of the regulation of expression of the genes encoding type I collagen is essential for understanding these various processes and the diseases that can affect them. The applicant has a long and successful track record in analyzing the 5' flanking sequence of the a1(I) collagen gene. As the applicant points out, numerous studies have tried to address the cell-specific regulation of expression of the type I collagen genes yet these mechanisms are still not understood. In particular the role of distal elements in the a1(I) collagen gene and of the chromatin structure is unknown. Thus, the long-term goal of this proposal is to understand at the molecular level, the complex mechanisms involved in the stage and tissue-specific regulation of the a1(I) collagen gene. The applicant proposes to achieve this goal of analyzing the role of chromatin structure and the nuclear matrix in a1(I) collagen regulation of expression. The five specific aims are: To identify regulatory elements that account for the high level of a1(I) collagen in cells that produce large amounts of type I collagen; to identify and analyze regulatory elements involved in the chromatin loop organization of the a1(I) collagen domain; to analyze the functions of distal regulatory elements in transgenic mice; to analyze a1(I) regulatory elements in normal development and differentiation and in fibrotic disorders.