Contraception by Blockade of Periovulatory Events in Primates

描述（由申请人提供）：俄勒冈州国家灵长类动物研究中心（ONPRC）提议建立一个U54避孕开发研究中心，旨在发现和开发新型避孕药，以防止成年雌性灵长类动物在月经周期中的一种或多种围排卵期事件。四个研究项目和一个动物核心利用旧大陆（猕猴）猴来产生关于防止女性卵母细胞受精的潜在模式的新信息和概念证明。项目一，“卵母细胞成熟的控制”，将解决新的卵泡细胞和卵母细胞衍生的蛋白质控制卵母细胞的核和细胞质成熟的假设，并可以被利用来阻止卵子及时成熟，从而在月经周期中生育。项目二“卵丘-卵母细胞扩增的控制”，将分析颗粒/卵丘细胞和卵母细胞衍生的蛋白控制卵丘-卵母细胞扩增（C-OE），并测试特异性拮抗剂是否会破坏C-OE，从而破坏雌性猴子的卵子释放和生育能力。项目三，“卵泡破裂的控制”，探讨灵长类动物排卵期卵泡中表达的独特蛋白酶，以及它们的抑制是否会阻止月经周期中的排卵，从而阻止卵子释放和生育。项目四，“配子运输和受精的控制”，测试了雌激素作用对正常输卵管和宫颈功能至关重要的假设，因此选择性雌激素受体调节剂（SERM）会破坏生殖道内卵母细胞和精子的运输，从而阻止猕猴的受精和生育。虽然每个项目都将进行药物作用的基本发现和阐明，但有希望的药物将在非人类灵长类动物避孕核心中进行避孕功效和可逆性测试，在对照试验中使用小群体（10只雌性到1-2只雄性）的猕猴。行政核心将促进避孕研究方面的中心内部和中心之间的合作，并促进与人口与发展中心项目干事的联络。U54 CDRC将与ONPRC和俄勒冈健康与科学大学（OHSU）现有的卓越生殖研究（包括几个可用的研究服务核心和与制药业的现有联系）协同作用，促进与妇女测试和配制新型避孕药具直接相关的转化研究。

DESCRIPTION (provided by applicant): The Oregon National Primate Research Center (ONPRC) proposes to establish a U54 Contraceptive Development Research Center that targets the discovery and development of novel contraceptive agents that prevent one or more periovulatory events in adult, female primates during the menstrual cycle. Four research projects and one animal core utilize Old World (macaque) monkeys to generate new information and proof-of-concept regarding potential modalities for preventing oocyte fertilization, and hence fertility, in women. Project I, "Control of Oocyte Maturation", will address the hypothesis that novel follicle cell- and oocyte-derived proteins control nuclear and cytoplasmic maturation of the oocyte, and can be exploited to prevent timely egg maturation and hence fertility during the menstrual cycle. Project II, "Control of Cumulus- Oocyte Expansion", will analyze the granulosa/cumulus cell- and oocyte-derived proteins controlling cumulus-oocyte expansion (C-OE) and test whether specific antagonists disrupt C-OE and hence egg release and fertility in female monkeys. Project III, "Control of Follicle Rupture", explores the unique proteases expressed in the periovulatory follicle in primates, and whether their inhibition will prevent ovulation and hence egg release and fertility during the menstrual cycle. Project IV, "Control of Gamete Transport and Fertilization", tests the hypothesis that estrogen action is essential for normal oviductal and cervical function, such that a selective estrogen receptor modulator (SERM) will disrupt oocyte and sperm transport within the reproductive tract, and hence prevent fertilization and fertility in macaques. Whereas basic discovery and elucidation of drug action will be pursued in each Project, promising agents will be tested in the Nonhuman Primate Contraceptive Core for contraceptive efficacy and reversibility, using small groups (10 females to 1-2 males) of macaques in controlled trials. The Administrative Core will foster intra- and inter-center cooperation in contraceptive research, and liaison with the NICHD Project Officer. The U54 CDRC will synergize with existing excellence in reproductive research at ONPRC and the Oregon Health & Science University (OHSU), including several available research service cores and existing ties with the pharmaceutical industry, to promote translational research of direct relevance to testing and formulating novel contraceptives in women.