The purpose of this grant is to explore the hypotheses that selective expression of meiosis activating and inhibiting genes exists in the primate ovary, and that targeting these genes will lead to the development of gamete-based, nonhomornal contraceptive agents.
The Specific Aims are: (1) to evaluate the expression of genes involved in the resumption of meiosis in the primate ovary;and to investigate the in vitro functions of selected candidates. The goal of this aim is to characterize the spatiotemporal expression pattern of candidate genes (i.e., INSL3-LGR8, WEE1B, and oocyte-specific NALPs) involved in oocyte maturation in the macaque ovary. An additional goal will be to document in vitro functions of oocyte-specific candidates by using INSL3 analogs and RNA interference (RNAi) to generate LGR8, WEE1B, and NALPs gene knockdowns in macaque ooocytes. (2) To determine if selected agents can disrupt timely oocyte maturation without altering other ovarian functions in rhesus macaques. The goal of this aim is to document that INSL3 agonist/antagonist or WEE1 B-specific siRNA will disrupt timely oocyte maturation independent of an ovulatory stimulus, so that fertilization does not occur in vitro. And (3) To determine whether selected candidates (e.g. INSL3 analogs) can function as contraceptive agents in regularly cycling rhesus monkeys in group-mating situations. The goal of this aim is to document the efficacy and practicality of the strategy as a potential contraceptive. Experimental designs will include: characterization of gene products (mRNA and protein) in somatic and germ cells in the macaque ovary (Aim 1), in vitro RNAi to deplete meiotic inhibitors (e.g., WeelB) and activators (e.g. LGR8) in the oocyte to observe the progress of oocyte maturation (Aim1), in vitro incubation of immature oocytes and granulosa cells with meiotic inhibitors and activators (Aim 1), in vivo administration of INSL3/its antagonist and WEE IB-specific siRNA to monkeys during COv and natural menstrual cycles, followed by follicular aspiration to assess oocyte maturation and fertilizability in vitro, plus endocrine and toxicity measurments (Aim 2), and chronic administration of INSL3 or its inhibitor to fertile females in a breeding colony with fertile males to assess contraceptive efficacy and long term toxicity (Aim 3). This approach is expected to provide a foundation for future Phase 1 trials of INSL3 in humans;and to identify other oocyte-specific novel gene products as potential future contraceptive targets.

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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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
Slayden, Ov Daniel; Friason, Francis Kathryn E; Bond, Kise Rosen et al. (2018) Hormonal regulation of oviductal glycoprotein 1 (OVGP1; MUC9) in the rhesus macaque cervix. J Med Primatol 47:362-370
Stouffer, Richard L; Woodruff, Teresa K (2017) Nonhuman Primates: A Vital Model for Basic and Applied Research on Female Reproduction, Prenatal Development, and Women's Health. ILAR J 58:281-294
Zhu, Jin-Yi; Cuellar, Rebecca A; Berndt, Norbert et al. (2017) Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors. J Med Chem 60:7863-7875
Slayden, Ov D; Lee, Dong Ock; Yao, Shan et al. (2016) Polidocanol induced tubal occlusion in nonhuman primates: immunohistochemical detection of collagen I-V. Contraception 94:521-526
Hanna, Carol B; Yao, Shan; Ramsey, Cathy M et al. (2015) Phosphodiesterase 3 (PDE3) inhibition with cilostazol does not block in vivo oocyte maturation in rhesus macaques (Macaca mulatta). Contraception 91:418-22
Jensen, Jeffrey T; Hanna, Carol; Yao, Shan et al. (2015) Characterization of tubal occlusion after transcervical polidocanol foam (PF) infusion in baboons. Contraception 92:96-102
Peluffo, M C; Stanley, J; Braeuer, N et al. (2014) A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques. Hum Reprod 29:1400-12
Peluffo, Marina C; Hennebold, Jon D; Stouffer, Richard L et al. (2013) Oocyte maturation and in vitro hormone production in small antral follicles (SAFs) isolated from rhesus monkeys. J Assist Reprod Genet 30:353-9
Edelman, Alison B; Jensen, Jeffrey T; Doom, Carmen et al. (2013) Impact of the prostaglandin synthase-2 inhibitor celecoxib on ovulation and luteal events in women. Contraception 87:352-7

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