IGFS AS REGULATORS OF ENDOCRINE CELL GROWTH & FUNCTION

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We will investigate the role of insulin-like growth factors (IGFs) in the control of growth and differentiated function in cells from two endocrine glands, the thyroid and the ovary. It is based on the hypothesis that IGFs act both alone and in concert with tissue specific growth factors to regulate a range of biological effects in many cell types, including those with highly specialized funciton, i.e., differentiated endocrine epithelial cells. Thus, IGFs are "non-specific" growth factors that act alone and with other growth factors in cells of mesenchymal origin but with specific trophic hormones in highly differentiated cells such as those from the thyroid and the ovary. The experimental design involves the use of a cloned line of thyroid follicular cells, FRTL5, that maintains thyroid differentiated function in vitro and the use of freshly obtained human ovarian granulosa cells. The goals of the project will be to: 1) identify the cell-surface membrane receptors for IGF-I, IGF-II, and insulin on FRTL5 cells and ovarian granulosa cells; 2) probe which of these receptors mediate IGF-I stimulated biological effects in these two cells types with polyclonal anti-insulin receptor sera and a monoclonal anti-type I IGF receptor antibody (Alpha IR-3); 3) investigate the interactions of IGFs with the specific trophic pituitary hormones for each of the two cell types, TSH for FRTL5 cells and FSH for the granulosa cells, over a range of biological activities; 4) study the interaction of IFGs with a series of other tissue growth factors in FRTL5 cells as a means of probing post-receptor mechanisms of action; 5) study specific protooncogene expression in FRTL5 cells in response to IGFs, PDGF, and TSH; and 6) establish long-term cultures of human ovarian granulosa cells that will be suitable for studying cellular proliferation as well as differentiated function. We will probe several potential "second messenger" pathways including the IGF-I receptor tyrosine kinase and the adenylate cyclase system. We anticipate that these studies will provide important information both about the role of IGFs in regulating endocrine cell growth and function and about the mechanisms by which IGFs stimulate a proliferative response in a wide variety of cells.