NOVEL CONTRACEPTIVES: CONTROL OF OOCYTE MATURATION

新型避孕药：控制卵母细胞成熟

• 批准号: 8357772
• 负责人: Xuemei Wu
• 金额: $ 3.63万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357772
• 关键词: Contraceptive Agents; Cyclic AMP; Development; Down-Regulation; Enzymes; Funding; Gene Expression; Gene Targeting; Genes; Germ Cells; Grant; In Vitro; Lead; Ligands; Macaca; Macaca mulatta; Meiosis; Mus; National Center for Research Resources; Oocytes; Ovarian; Ovary; Partner in relationship; Primates; Principal Investigator; Rana; Research; Research Infrastructure; Resources; Signal Pathway; Source; Testis; United States National Institutes of Health; base; blastocyst; cost; inhibitor/antagonist; novel; oocyte maturation; overexpression; receptor; selective expression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 该项目的目的是探索在灵长类动物卵巢中存在选择性表达和抑制基因的选择性表达的假设，而靶向这些基因的基因将导致基于配子的，非霍尼的避孕剂的发展。具体目的是：（1）评估在灵长类动物卵巢中恢复减数分裂的基因的表达，并研究选定候选者的体外功能； （2）确定选定的药物是否会破坏及时的卵母细胞成熟，而不会改变恒河猕猴中其他卵巢功能； （3）确定选定的候选者是否可以在群体交配情况下定期循环恒河猴中的避孕剂起作用。 在对猕猴卵巢中INSL3-RXFP2信号通路的表达和功能进行彻底分析之后，我们得出的结论是，配体 - 受体对对恒河猕猴中的卵母细胞成熟不是必不可少的。 因此，我们专注于新鉴定的卵母细胞特异性的减数分裂抑制剂，即先前在青蛙和小鼠中研究的WEE2。 WEE2主要在恒河猴中的卵母细胞和早期植入前胚胎中表达，并且仅在睾丸中弱检测到。 虽然WEE2的下调导致在存在高核细胞营地的情况下导致减数分裂恢复，但WEE2的过表达延迟了自发性卵母细胞的成熟。 我们目前正在研究该分子中的关键功能域，以期开发抑制或模仿WEE2活性的化合物。 此外，我们还在猕猴中的WEE2，cdc25的反破坏酶进行功能研究。