ANDROGEN RECEPTOR REGULATION IN OVARIAN GRANULOSA CELLS

描述：许多哺乳动物物种，包括人类，表达卵巢癌基因。 雄激素受体（AR）。 雄激素作用可能涉及10-15%的 女性不孕症假设是由于卵巢功能障碍，往往是 病因不明。 在大鼠中，卵巢颗粒细胞表达AR， 随着卵泡从小窦期到排卵前成熟， 阶段 垂体促性腺激素FSH在体内和体外调节卵巢AR， 体外 雄激素是颗粒细胞功能的重要调节因子， 包括类固醇生成和卵泡发育。 激素调节的卵巢AR表达可能具有重要的 生理和病理生理后果。 然而， 关于卵巢AR表达的分子基础。 部分地 表达的类固醇受体的特定同种型决定了它是否可以 作为转录激活因子或抑制因子。 有可能AR 同种型存在于哺乳动物卵巢中。 如果是这样的话， 监管和活动将产生新的见解的监管作用， 卵巢雄激素 这项研究的长期目标是更好地 了解雄激素在卵巢功能和疾病中的作用。 该提案将使用卵泡发育的良好表征模型， 雄性未成熟的雌性大鼠，以检查AR的调节 在颗粒细胞中。 该模型适用于生物化学和 分化功能和基因表达的分子分析。 卵泡及其颗粒细胞将被分离并用于研究两者 AR蛋白和mRNA体内和体外调节。 荷尔蒙 调节AR表达的因子将使用体外颗粒细胞 细胞培养 AR受两种雄激素的转录调节 蛋白激酶A/cAMP信号通路在其他组织中的作用。 大鼠颗粒细胞中AR的调节将使用转染进行研究 分析以定位AR启动子的转录调控区。 使用大鼠颗粒细胞模型，该建议的具体目标是 确定：1）体内表达的AR蛋白和mRNA同种型; 2） 体外调节AR基因表达的激素因子;和3） 调节AR转录的顺式元件和反式因子 表情

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.