Collagen is the predominant protein in the connective tissue of higher eukaryotes. There are five major collagen types, which appear to be the products of nine different structural genes. The major goal of this study is the identification of factors which determine the normal pattern of collagen gene expression during differentiation and development. These factors include intrinsic structural features of the genes, as well as extrinisic factors, which may interact to regulate the expression of the genes at the levels of transcription, RNA processing and translation. The four genes encoding the most abundant collagen subunits will be isolated and characterized, to permit identification of sequences which may be involved in selection of the appropriate genes for expression during tissue differentiation. We will also map the major and minor transcripts of each of the genes, and determine the functional roles of the two RNAs. We will attempt to identify nuclear factors involved in selection of the appropriate genes for transcription; such factors would presumably interact with the regulatory sequences in the structural genes themselves. Factors will also be identified which influence the rate of translation of collagen mRNAs in the cytoplasm (or which sequester them to prevent their translation). Considerable evidence has accumulated that all of these levels are involved in determining the appropriate patterns of collagen gene expression during differentiation and development. Finally, we will examine a variety of conditions in which the normal pattern of collagen gene expression is perturbed. These include several inherited connective tissue disorders in which mutations in the collagen genes lead to a disruption of the normal collagen phenotype. They also include in vitro manipulations of cells, particularly by viral transformation, causing them to lose their differentiated phenotype, manifested as a failure to synthesize the normal collagen type.
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