The Oregon National Primate Research Center (ONPRC), Oregon Health &Science University (OHSU) proposes to continue 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. Three research projects and one animal core will 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 (granulosa) cell- and oocyte-derived proteins control nuclear and cytoplasmic maturation of the oocyte, and can be exploited to prevent timely egg maturation and fertility during the menstrual cycle. Project II, "Control of Follicle Rupture and Cumulus-Oocyte Activities" will test whether specific antagonists of select granulosa- or oocyte derived proteins disrupt cumulus-oocyte expansion or ovulation, and hence egg release and fertility during the menstrual cycle. Project III, "Control of Gamete Transport and Fertilization" will investigate reversible and nonreversible methods to locally prevent sperm and oocyte transport in the reproductive tract, and hence fertilization and fertility in female macaques. Based on progress in the prior grant interval and continued basic discovery and elucidation of drug action, promising agents will be tested in the Nonhuman Primate Contraceptive Core for contraceptive efficacy, reversibility and side effects. Ongoing collaboration with colleagues at the University of Minnesota and Bayer Pharma AG (formerly Schering AG), Berlin will facilitate drug discovery, nonhuman primate testing, and ultimately early (Phase I) clinical trials. The Administrative Core will foster intra- and inter-center cooperation in contraceptive research, and liaison with NICHD, CRB project officers. The synergy between reproductive scientists and clinical researchers at ONPRC, OHSU, combined with active collaborations with colleagues in universities and pharmaceutical companies, provides a valuable opportunity to promote translational research in primates that's most relevant to developing novel, ovary/tract-based contraceptives for women.

Public Health Relevance

Population growth, significant numbers of unintended pregnancies and limitations of current methods provide a strong rationale for development of the next generation of contraceptives. Recent understanding of molecular and cellular events controlling fertility can now direct efforts to target key processes in the gonad and reproductive tract prior to fertilization. This center will use the primate model to identify and test drugs tha selectively block periovulatory events during the menstrual cycle, as a prelude to clinical trials n women.

Agency
National Institute of Health (NIH)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD055744-08
Application #
8699797
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Lee, Min S
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Portland
State
OR
Country
United States
Zip Code
97239
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Keator, Christopher S; Mah, Kuni; Ohm, Lindsay et al. (2011) Estrogen and progesterone regulate expression of the endothelins in the rhesus macaque endometrium. Hum Reprod 26:1715-28
Xu, Fuhua; Stouffer, Richard L; Muller, Jorg et al. (2011) Dynamics of the transcriptome in the primate ovulatory follicle. Mol Hum Reprod 17:152-65
Peluffo, Marina C; Murphy, Melinda J; Baughman, Serena Talcott et al. (2011) Systematic analysis of protease gene expression in the rhesus macaque ovulatory follicle: metalloproteinase involvement in follicle rupture. Endocrinology 152:3963-74
Peluffo, Marina C; Barrett, Susan L; Stouffer, Richard L et al. (2010) Cumulus-oocyte complexes from small antral follicles during the early follicular phase of menstrual cycles in rhesus monkeys yield oocytes that reinitiate meiosis and fertilize in vitro. Biol Reprod 83:525-32

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