The goals of this project are to determine the molecular basis for the expression of multiple insulin-like growth factor I (IGF I) receptor species in mammalian tissues and the functional importance of different IGF I receptors. Recent work from this laboratory has demonstrated two closely related but structurally distinct IGF I receptor proteins. One receptor, (the """"""""adult"""""""" type) is present at all developmental ages; the second receptor (the """"""""fetal"""""""" type) is selectively expressed early in development in most tissues. The fetal receptor has shown to differ from the adult IGF I receptor in that it is more heavily glycosylated, has a different primary structure, and its tyrosine kinase is activated by low concentrations of either insulin or IGF I. The differences between the fetal and adult IGF I receptors may be important in determining the rapid growth characteristics of fetal tissues and possibly the potent growth effects of insulin as well as IGF I. Additional recent work from this laboratory has also defined a site of alternative splicing in the IGF I receptor gene that leads to the formation of mRNA transcripts encoding a putative third type of IGF I receptor. The specific goals of the research in this proposal are: (1) to obtain cDNA newly defined splice variant, and possible other IGF I receptor species, (2) to investigate the hormone binding and functional properties of different IGF I receptor species in cultured cells transfected with specific IGF I receptor cDNAs, and (3) to investigate the hormone binding and functional properties of different IGF I receptors and the expression and function of different IGF I receptor proteins in human tissues. The planned studies should contribute significantly to our understanding of basic mechanisms that control receptor gene expression, the actions of IGF I during development, and the potential role of IGF I receptors in mediating growth responses to insulin. Interactions of insulin with specific IGF I receptor species, such as the fetal receptor, could have an important role in causing macrosomia and possibly developmental malformations in offspring of women with diabetes. Since individual IGF I receptor types may be selectively expressed in rapidly proliferating cells and tissues, an understanding of the functional properties of the different receptors may give insight into both normal and abnormal states of growth in many tissues.
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