ROLE OF THE BMP SYSTEM IN THE OVARY

雌二醇和孕酮的生物合成在周期的卵泡期分别受到刺激和抑制，但这种重要的生理差异调节机制尚不清楚。卵泡刺激素(FSH)刺激颗粒细胞产生雌二醇的作用已被证实，有人提出需要一种尚未确定的黄体生成抑制剂来抑制FSH诱导孕酮的产生。在初步研究中，我们获得了三个新的发现：1)大鼠卵巢中存在一个充满配体、受体和生物反应的骨形态发生蛋白(BMP)系统；2)BMP(BMP-4和BMP-7)在FSH存在的情况下，刺激原代培养的大鼠颗粒细胞中雌二醇的积累，但抑制孕酮的积累，这表明BMP可能是长期寻找的“黄体生成抑制物”；以及3)Folistatin可以通过形成不活跃的由Folistatin、BMP和IA型BMP受体组成的三聚体复合体来阻断BMP的作用，这表明已知在优势卵泡中强表达的FMP可能对卵巢的BMP功能起到拮抗作用。为了研究BMPs在卵泡发生中的作用以及卵泡抑素如何促进BMP的作用，提出了四个具体的目标。目的：研究发情周期和月经周期大鼠和人卵巢中BMP系统(配体、受体、结合蛋白)的特征。目的：探讨骨形态发生蛋白(BMPs)对大鼠和人颗粒细胞分化的调节作用。重点是探索BMPs调节颗粒细胞类固醇合成的分子机制。目的3：验证卵泡抑素在体外调节大鼠和人颗粒细胞对BMP依赖的细胞分化的假说。目的4：通过检验体内BMP是黄体化抑制因子的假说，建立BMP功能的生理学相关性。这些研究结果可能证明BMPs是生理上重要的黄体生成抑制剂，而卵泡抑素在抑制大鼠和人颗粒细胞的BMP反应中起着新的作用。

Estradiol and progesterone biosynthesis are stimulated and inhibited, respectively, during the follicular phase of the cycle, but the mechanisms underlying this physiologically important differential regulation are unknown. The role of FSH in stimulating estradiol production by granulosa cells is well established, and it has been proposed that a yet to be identified "luteinizing inhibitor" is needed to inhibit FSH-induced progesterone production. In preliminary studies, we made three novel findings: 1) a bone Morphogenetic Protein (BMP) system replete with ligands, receptors, and biological responses is present in rat ovaries; 2) BMPs (BMP-4 and -7) stimulate estradiol but inhibit progesterone accumulation in primary cultures of rat granulosa cells in the presence of FSH, suggesting BMPs may be the long sought "luteinizing inhibitor"; and 3) follistatin can block BMP action by forming an inactive trimeric complex of follistatin, BMP and type IA BMP receptor, suggesting that follistatin, which is known to be strongly expressed in dominant follicles, may exert an antagonistic effect on BMP function in the ovary. To investigate the role of BMPs in folliculogenesis and how follistatin contributes to BMP action, four specific aims are proposed. Aim1: To characterize the BMP system (ligands, receptors, binding proteins) in rat and human ovaries during the estrous and menstrual cycles, respectively. Aim2: To explore the role of BMPs in regulating the cytodifferentiation of rat and human granulosa cells. Emphasis will be placed on exploring the molecular mechanisms by which BMPs regulate steroidogenesis in granulosa cells. Aim3: To test the hypothesis that follistatin modulates extracellular BMP-dependent cytodifferentiation in rat and human granulosa cells in vitro Aim 4: To establish the physiological relevance of BMP functions by testing the hypothesis that BMP is a luteinization inhibitor in vivo. The results of these proposed studies may demonstrate that BMPs are physiologically important luteinizing inhibitors and that follistatin plays a novel role in inhibiting BMP responses in rat and human granulosa cells.