NOVEL CONTRACEPTIVES: CONTROL OF OOCYTE MATURATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本项目的目的是探索灵长类动物卵巢中存在减数分裂激活和抑制基因的选择性表达，以及靶向这些基因将导致开发基于配子的非同源避孕药的假设。 具体目标是：（1）评估灵长类卵巢中参与减数分裂恢复的基因的表达;并研究所选候选物的体外功能;（2）确定所选试剂是否可以破坏恒河猴中卵母细胞的适时成熟而不改变其他卵巢功能;以及（3）确定所选候选物（例如胰岛素样3，INSL 3）是否可以在群体交配情况下在定期循环的恒河猴中起避孕剂的作用。 实验设计包括：猕猴卵巢中体细胞和生殖细胞中基因产物的表征（Aim 1），体外RNA干扰（RNAi）以耗尽减数分裂抑制剂（例如，WeelB）和活化剂（例如LGR 8）以观察卵母细胞成熟的进展（Aim 1），在控制排卵（COv）和自然月经周期期间向猴体内施用INSL 3/其拮抗剂和WEE 1B特异性siRNA，随后评估卵母细胞成熟和体外受精能力，加上内分泌和毒性测量（Aim 2），以及向具有能育雄性的繁殖群体中的能育雌性长期施用INSL 3或其抑制剂以评估避孕功效和长期毒性（目的3）。这种方法有望为未来的人类INSL 3 1期试验提供基础;并确定其他卵母细胞特异性新基因产物作为潜在的避孕靶点。

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.