Contraception by Blockade of Periovulatory Events in Primates

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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.