NOVEL CONTRACEPTIVES: CONTROL OF FOLLICULAR MATURATION AND RUPTURE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 雌性哺乳动物卵巢的主要功能是在动物的生殖寿命期间释放可受精的卵母细胞。 这是通过排卵过程实现的，其中完全发育的卵泡在周期中期促性腺激素激增后破裂，释放卵丘-卵母细胞复合体（COC）进入生殖道并可能受精。 然而，卵泡破裂和COC从卵泡内（颗粒）细胞层脱落需要通过复杂的蛋白酶系统进行显着重塑。 脱落之前，细胞与细胞之间的接触必须消失，卵丘细胞之间形成富含透明质酸的细胞外基质，从而导致COC的大量“扩张”。 此外，最近从非灵长类动物物种的数据表明，卵丘卵母细胞扩增（C-OE）涉及卵母细胞，颗粒/卵丘，和血清衍生因子之间的复杂的相互作用，如有针对性地破坏关键成分损害排卵和受精。 这些研究结果表明，有可能选择性地抑制卵泡蛋白水解，C-OE，卵母细胞释放，因此生育能力，而不改变女性生殖的其他方面，包括卵巢/月经周期。 因此，本项目的目的是确定蛋白酶，卵母细胞和颗粒/卵丘衍生蛋白参与C-OE是合适的目标，在灵长类动物的生育力控制。 迄今为止的进展表明，蛋白酶的金属超家族是排卵前表达的主要蛋白水解酶，抑制它们的活性可防止卵泡破裂和卵母细胞的释放。 此外，最近的研究表明，前列腺素E2用于启动恒河猴COC中的分子过程（例如，透明质酸合成）。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The principal function of the ovary in female mammals is to release a fertilizable oocyte during the animal's reproductive lifespan. This is achieved through the process of ovulation, wherein a fully-developed follicle ruptures following the mid-cycle gonadotropin surge, releasing the cumulus-oocyte complex (COC) for passage into the reproductive tract and possible fertilization. However, follicle rupture and detachment of the COC from the inner (granulosa) cell layer of the follicle requires significant 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 "expansion" of the COC. 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 suggest 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 determine if proteases, oocyte- and granulosa/cumulus-derived proteins involved in C-OE are suitable targets for the control of fertility in primates. Progress to date has revealed that the metallo- superfamily of proteases are the predominant proteolytic enzymes expressed prior to ovulation and that inhibition of their activity prevents follicle rupture and the release of an oocyte. Furthermore, recent studies have revealed that prostaglandin E2 serves to initiate molecular processes in rhesus macaque COCs (e.g., hyaluronan synthesis) required for C-OE.