Correct spatial and temporal production of structurally normal collagens plays a critical role in the development and growth of the organism. Understanding the function of collagen proteins and the regulation of collagen genes is therefore an important prerequisite to decipher the etiopathogenesis of connective tissue disorders. The long-term goal of the applicant's research program is to characterize the genetic factors and molecular mechanisms responsible for tissue-specific assembly and function of collagenous macroaggregates. Toward this end, three major aims are proposed: 1) To elucidate how type I collagen production is modulated by antagonistic cytokines implicated in matrix remodeling. The components of a transcriptional complex of the human a2(I) collagen gene which mediates the action of transforming growth factor beta1 and tumor necrosis factor alpha will be cloned. 2) To characterize which DNA elements and nuclear factors control overlapapplicantng and mutually exclusive synthesis of types V and XI collagen chains. A combination of functional and DNA-binding assays will be used to dissect the cis-acting sequences and identify the trans-acting factors responsible for cell type-specific expression of the a2(V) and a1(XI) collagen genes. 3) To determine the function of the newly discovered type XIX collagen. The a1(XIX) collagen gene will be mutated by homologous recombination in mouse embryonic stem cells and the consequences for the development, growth and fitness of the animals will be examined. The results of these experiments will increase understanding of how collagens contribute to the assembly and function of the extracellular matrix in normal and diseased conditions.
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