ROLE OF THE BMP SYSTEM IN THE OVARY

在周期的卵泡期，雌二醇和孕酮的生物合成分别受到刺激和抑制，但这种生理上重要的差异调节的机制尚不清楚。 FSH在刺激颗粒细胞产生雌二醇中的作用已得到充分证实，有人提出需要一种尚未鉴定的“黄体化抑制剂”来抑制FSH诱导的孕酮产生。在前期的研究中，我们有三个新的发现：1）大鼠卵巢中存在一个骨形态发生蛋白（BMP）系统，该系统具有丰富的配体、受体和生物学反应; 2）（BMP-4和BMP-7）在FSH存在下刺激大鼠颗粒细胞原代培养物中雌二醇的积累，但抑制孕酮的积累，这表明BMP可能是长期寻找的“黄体化抑制剂”;卵泡抑素可通过形成卵泡抑素、BMP和IA型BMP受体的失活三聚体复合物来阻断BMP的作用，这表明已知在优势卵泡中强烈表达的卵泡抑素可能对卵巢中BMP的功能发挥拮抗作用。 为了研究BMP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。目标1：分别在动情周期和月经周期期间表征大鼠和人卵巢中的BMP系统（配体、受体、结合蛋白）。目的2：探讨骨形成蛋白（BMPs）对大鼠和人卵巢颗粒细胞分化的调控作用。 重点将放在探索骨形态发生蛋白调节颗粒细胞类固醇生成的分子机制。目标3：为了测试的假设，卵泡抑素调节细胞外BMP-依赖的细胞分化在大鼠和人类颗粒细胞在体外目的4：为了建立BMP功能的生理相关性，通过测试的假设，即BMP是一种体内黄体化抑制剂。这些拟议的研究结果可能表明，骨形态发生蛋白是生理上重要的黄体化抑制剂，卵泡抑素在抑制大鼠和人类颗粒细胞的骨形态发生蛋白反应中发挥了新的作用。

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.