ANDROGEN RECEPTOR REGULATION IN OVARIAN GRANULOSA CELLS

描述：许多哺乳动物，包括人类，都有卵巢表达

DESCRIPTION: Many mammalian species, including humans, express ovarian androgen receptor (AR). Androgen action may be involved in the 10-15% of female infertility hypothesized to be due to ovarian dysfunction, often of unknown etiology. In rats, ovarian granulosa cells express AR and expression decreases as follicles mature from small antral to preovulatory stages. The pituitary gonadotropin FSH regulates ovarian AR in vivo and in vitro. Androgens are important regulators of granulosa cell function, including steroidogenesis and follicular development. Hormonally-regulated ovarian expression of AR may have important physiological and pathophysiological consequences. However, little is known concerning the molecular basis of ovarian AR expression. In part, the particular isoform of a steroid receptor expressed determines whether it may act as a transcriptional activator or repressor. It is possible that AR isoforms exist in the mammalian ovary. If so, an understanding of their regulation and activity will yield new insights into the regulatory role of ovarian androgens. The long-term objectives of this study are to better understand the role of androgens in ovarian function and disease. This proposal will use a well-characterized model of follicular development, the hormonally-primed immature female rat, to examine the regulation of AR in granulosa cells. This model is amenable to both biochemical and molecular analyses of differentiated function and gene expression. Follicles and their granulosa cells will be isolated and used to study both in vivo and in vitro regulation of AR protein and mRNA. The hormonal factors regulating AR expression will be identified using in vitro granulosa cell cultures. AR is regulated transcriptionally by both androgens themselves and the protein kinase A/cAMP signaling pathway in other tissues. Regulation of AR in rat granulosa cells will be studied using transfection assays to map the transcriptional regulatory region of the AR promoter. Using a rat granulosa cell model, this proposal's specific aims are to determine: 1) the AR protein and mRNA isotypes expressed in vivo; 2) the hormonal factors regulating AR gene expression in vitro; and 3) the cis-elements and trans-factors mediating transcriptional regulation of AR expression.