NOVEL CONTRACEPTIVES: CONTROL OF FOLLICULAR MATURATION AND RUPTURE

新型避孕药：控制卵泡成熟和破裂

• 批准号: 8357771
• 负责人: Jon D Hennebold
• 金额: $ 3.63万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357771
• 关键词: Animals; Cells; Complex; Contraceptive Agents; Contraceptive methods; Data; Dinoprostone; Extracellular Matrix; Female; Fertility; Fertilization; Funding; Gonadotropins; Grant; Hyaluronan; Longevity; Macaca mulatta; Mammals; Molecular; National Center for Research Resources; Oocytes; Ovarian; Ovary; Ovulation; Ovulation Inhibition; Peptide Hydrolases; Periodicity; Primates; Principal Investigator; Process; Proteins; Proteolysis; Reproduction; Research; Research Infrastructure; Resources; Rupture; Serum; Source; System; United States National Institutes of Health; cost; granulosa cell; novel; prevent; reproductive

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 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，在排卵过程中，成熟的卵泡在周期中期促性腺激素激增后破裂，释放出卵丘-卵母细胞复合物 (COC)，进入生殖道并可能受精。 然而，卵泡破裂以及 COC 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着重塑。 在脱离之前，细胞与细胞接触的丧失以及卵丘细胞之间富含透明质酸的细胞外基质的形成，导致 COC 的大幅“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/卵丘和血清衍生因子之间复杂的相互作用，因此关键成分的有针对性的破坏会损害排卵和受精。 这些发现表明，有可能选择性地抑制卵泡蛋白水解、C-OE、卵母细胞释放，从而抑制生育力，而不改变女性生殖的其他方面，包括卵巢/月经周期。 因此，该项目的目标是确定参与 C-OE 的蛋白酶、卵母细胞和颗粒/卵丘衍生蛋白是否是控制灵长类动物生育力的合适靶标。 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，抑制其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 可启动恒河猴 COC 中 C-OE 所需的分子过程（例如透明质酸合成）。