An important role of the ovulatory gonadotropin surge in the ovary is to promote the process called cumulusoocyte expansion (C-OE);this process results in detachment of the cumulus-oocyte complex from the follicle wall and hence the subsequent release of a fertilizable egg after follicle rupture. Recent data from nonprimate species indicate that C-OE involves a complex interaction between oocyte-, granulosa/cumulus-, and serum-derived factors, such that targeted disruption of key components impairs ovulation and fertilization. However, the expression and role of these or other novel factors in C-OE in primates is unknown. As part of the U54 CDRC application entitled, """"""""Contraception by Blockade of Periovulatory Events in Primates"""""""", this project will test the hypothesis that oocyte- and granulosa/cumulus cell-derived proteins control C-OE in primates, and that blockade of their synthesis or action will prevent timely C-OE, oocyte release, and fertility in Old World (macaque) monkeys during the menstrual cycle. Based on preliminary studies, further experiments are planned to:
(Aim No. 1) Evaluate gene/protein expression in the macaque cumulus-oocytecomplex during the periovulatory interval;
(Aim No. 2) Determine whether blockade of expression or action of granulosa/cumulus-oocyte factors prevents C-OE in vitro and in vivo;and then (Aim No. 3) Assess specific antagonists of C-OE as contraceptives in adult, female macaques during the menstrual cycle. Periovulatory follicles, folicular fluid and cumulus-oocyte complexes from controlled ovulation (COv), and controlled ovarian stimulation (COS) cycles will be analyzed for mRNA and protein expression by macaque gene array, in situ hybridization, immunocytochemistry and immunoassay. Based on preliminary data, initial studies will focus on blockade of early (via a prostaglandin E receptor antagonist) and later (by antagonism of the secreted protein, tumor necrosis factor alpha-induced protein-6, TNFAIP-6) events in the prostaglandin cascade. Further studies are planned as additional pathways are elucidated, e.g., the Growth and Differentiation Factor (GDF)-9/Bone Morphogenetic Protein (BMP)-15 cascade, in macaque cumulus-oocyte complexes. Trials with C-OE antagonists will be performed in the Nonhuman Primate Contraceptive Core. This approach from basic discovery to proof-of-concept should identify C-OE inhibitors as possible candidates for further development and testing as novel, gamete/ovary-based contraceptives in women.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1)
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Oregon Health and Science University
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Jakkaraj, Sudhakar; Young Jr, Victor G; Georg, Gunda I (2018) Syntheses of PDE3A inhibitor ORG9935 and determination of the absolute stereochemistries of its enantiomers by X-ray crystallography. Tetrahedron 74:2769-2774
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