This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this project 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;(2) to determine if selected agents can disrupt timely oocyte maturation without altering other ovarian functions in rhesus macaques;and (3) to determine whether selected candidates (e.g. insulin-like 3, INSL3) can function as contraceptive agents in regularly cycling rhesus monkeys in group-mating situations. Experimental designs include: characterization of gene products in somatic and germ cells in the macaque ovary (Aim 1), in vitro RNA interference (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 vivo administration of INSL3/its antagonist and WEE1B-specific siRNA to monkeys during controlled ovulation (COv) and natural menstrual cycles, followed by assessment of 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 contraceptive targets.
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