NOVEL CONTRACEPTIVES: CONTROL OF OOCYTE MATURATION

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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 can function as contraceptive agents in regularly cycling rhesus monkeys in group-mating situations. After a thorough analysis on the expression and function of INSL3-RXFP2 signaling pathway in the macaque ovary, we concluded that the ligand-receptor pair is not essential for oocyte maturation in rhesus macaques. Thus, we focused on a newly identified oocyte-specific meiotic inhibitor, namely WEE2, that is previously studied in the frog and mouse. WEE2 is predominantly expressed in the oocyte and early preimplantation embryos in rhesus monkeys, and only weakly detectable in the testis. While down-regulation of WEE2 caused leaky meiosis resumption in the presence of high intra-oocyte cAMP, overexpression of WEE2 delayed spontaneous oocyte maturation. We are currently investigating key functional domains in the molecule, in hope of developing compounds that inhibit or mimic the activity of WEE2. In addition, we are also conducting functional studies on a counteracting enzyme of WEE2, CDC25, in the macaque oocytes.