This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.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 candidate molecules can be tested for contraceptive potential using an established sequence of in vitro and in vivo experiments culminating in a contraceptive trial in breeding groups of macaques.
The Specific Aims are: (1) to identify ovary-expressed genes that may be related to oocyte maturation; and to investigate the in vitro functions of selected candidates (e.g, INSL3-LGR8 pathway, WEE1B, and oocyte-specific NLRPs), (2) to determine if selected candidates can be used as contraceptive agents in rhesus monkeys in vivo, and (3) to determine whether selected candidates (e.g., INSL3) can function as a contraceptive agents in regularly cycling rhesus monkeys in paired mating situations. Experimental designs will include: characterization of gene products (mRNA and protein) in the macaque ovary, in vitro RNAi in the oocyte and in vitro incubation of immature oocytes and granulosa cells with meiotic inhibitors and activators (Aim 1); in vivo administration of INSL3 or its antagonist to monkeys during controlled ovarian stimulation (COS) and spontaneous menstrual cycles, plus endocrine and toxicity measurements (Aim 2); and chronic administration of INSL3 or its inhibitor to fertile females in a breeding colony to assess contraceptive efficacy and long term toxicity (Aim 3). This approach is expected to provide a foundation for future trials of INSL3 in humans; and to identify other oocyte-specific novel gene products as potential future contraceptive targets.
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