NOVEL CONTRACEPTIVES: CONTROL OF FOLLICULAR MATURATION AND RUPTURE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 雌性哺乳动物卵巢的主要功能，尽管产生性类固醇激素，但在动物的生殖寿命期间，及时释放可受精的配子，即卵母细胞或卵。这一功能是通过排卵过程实现的，在排卵过程中，完全发育的卵泡在排卵促性腺激素激增的作用下破裂，并释放卵丘-卵母细胞复合体，进入生殖道并可能受精。然而，卵泡破裂和卵丘-卵母细胞复合体从卵泡内(颗粒)细胞层脱离需要通过复杂的蛋白酶系统进行显著的细胞重组和细胞外基质重塑。在分离之前，必须失去细胞与细胞的接触，并在卵丘细胞之间形成富含透明质酸的细胞外基质，导致卵丘-卵母细胞复合体的大量增加或“扩张”。此外，来自非灵长类物种的最新数据表明，卵丘-卵母细胞扩张(C-OE)涉及卵母细胞、颗粒/卵丘和血清来源的因子之间的复杂相互作用，因此有针对性地破坏关键成分会损害排卵和受精。这些发现与新的概念是一致的，即可以选择性地抑制卵泡蛋白分解、C-OE、卵母细胞释放，从而抑制生育，而不改变女性生殖的其他方面，包括卵巢/月经周期。因此，本项目的目的是验证一种假设，即在灵长类动物中，蛋白水解酶、卵母细胞和颗粒/卵丘来源的蛋白质控制卵泡破裂和C-OE。此外，还将确定阻断它们的合成或作用是否会阻止旧大陆(猕猴)猴子及时的C-OE、卵母细胞释放和怀孕。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The principal function of the ovary in female mammals, the production of sex steroid hormones notwithstanding, is to release the fertilizable gamete, the oocyte or egg, in a timely manner during the animal's reproductive lifespan. This function is achieved through the process of ovulation, wherein a fully-developed follicle ruptures in response to the actions of the ovulatory gonadotropin surge, and releases the cumulus-oocyte complex for passage into the reproductive tract and possible fertilization. However, follicle rupture and detachment of the cumulus-oocyte complex from the inner (granulosa) cell layer of the follicle requires significant cellular reorganization and extracellular matrix remodeling via a complex system of proteases. Detachment must be preceded by loss of cell-cell contacts and formation of a hyaluronan-rich extracellular matrix between cumulus cells, resulting in a large increase or "expansion" of the cumulus-oocyte complex. Furthermore, recent data from nonprimate species indicate that cumulus-oocyte expansion (C-OE) involves complex interactions between oocyte-, granulosa/cumulus-, and serum-derived factors, such that targeted disruption of key components impairs ovulation and fertilization. These findings are consistent with the novel concept that it is possible to selectively inhibit follicle proteolysis, C-OE, oocyte release, and hence fertility, without altering other aspects of female reproduction, including ovarian/menstrual cyclicity. Thus the objective of this project is to test the hypothesis that proteases, oocyte- and granulosa/cumulus-derived proteins control follicle rupture and C-OE in primates. Furthermore, it will be determined whether blockade of their synthesis or action will prevent timely C-OE, oocyte release and pregnancy in Old World (macaque) monkeys.