The goals of the investigation are to study the control of insulin-like growth factor I (IGF I) biosynthesis in model cell culture systems and in the whole animal. Based on our preliminary observations the human IGF I gene gives rise by alternative RNA processing to two messenger RNA transcripts encoding different peptide precursors. These initial studies suggest that regulatory mechanisms controlling IGF I biogenesis include both tissue-specific RNA splicing and tissue-specific protein processing. The putative regulatory steps may be responsible for unique IGF I peptide species subserving different roles as either hormones or autocrine/paracrine growth stimulators. In order to study the regulation of IGF I biosynthesis, I propose the following three specific objectives: (1) To define the protein precursors, processing intermediates, and steps leading to the secretion of mature IGF I by using the techniques of gene transfer to introduce IGF I complementary DNAs (cDNAs) into hepatocyte and fibroblast cell lines, and an inducible gene expression system to amplify IGF I biosynthesis. (2) To determine by molecular cloning the structure and sequence of rat IGF I messenger RNAs and gene. (3) To study the regulation of IGF I gene expression during growth and development in the rat using the homologous cDNAs and gene as probes, in particular to analyze the role of growth hormone in enhancing IGF I biosynthesis.
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