This proposal seeks to develop a more complete and integrated picture of the ovarian IGF system by developing a deeper understanding of three key components, IGF-1, IGFBP-2, and IGFBP-3 and their interaction. Central investigative targets regarding IGF-1 are the hormonal control of its biosynthesis in ovarian cells. These studies will establish the mechanism of action of FSH, CAMP and GH, the principal stimulators of this gene, in terms of qualitative and quantitative aspects of IGF-1 gene transcription. These studies will entail mapping of hormone responsive sequences in the IGF-1 gene promoter and the mature peptide in culture. The action of IGFBP-2 and -3 will be established by examining their interactions with ovarian target cells and their effects on a series of ovary specific cell functions. Finally, the validity of hypotheses generated from these in vitro studies will be tested in transgenic mice bearing transgenes which either knockout or amplify the expression of these key components. These results may have significant implications for disease processes in humans. Attempts to manipulate the IGF system in patients have already been introduced into infertility clinics. Data from in vitro and histochemical studies in humans have implicated distortions of this system in disease processes such as polycystic ovary syndrome. Our own studies suggest many similarities of the animal models used to humans.
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