Hippo信号通路在调控哺乳动物原始卵泡启动中的作用及机制研究

阐明原始卵泡启动的分子机制对于防治女性不孕症和卵巢早衰具有重要意义。最近研究表明，卵巢皮层密度变化能触发原始卵泡的启动，而在果蝇中的研究显示由多个癌基因（Mst/Lats/Yap）参与的Hippo信号通路可感知卵巢细胞密度的变化。我们前期实验发现Yap在小鼠原始卵泡启动前后有显著性差异，故我们假设Hippo信号通路可能是哺乳动物原始卵泡启动的触发机制。本课题拟以小鼠和人卵巢组织为实验对象，分析Hippo通路相关信号分子的表达与原始卵泡池大小变化的时序相关性；通过基因工程手段调控Hippo通路，研究其对原始卵泡启动的影响及相关机制；进一步观察调控下的原始卵泡后期发育及受精潜能。申请人有良好的卵泡发育调控研究基础（Reprod Biol Endocrinol，2010；DNA and Cell Biol, 2012），相信本课题将为诊疗女性相关生育疾病提供有价值的理论依据。

Clarifying the molecular mechanisms by which the initiation of primordial follicles is regulated is crucial for the prevention and treatment of female infertility and premature ovarian failure. Recent reports have shown that changes of ovarian cortical density could trigger the onset of the primordial follicle. On the other hand, Hippo signaling pathway which consists of several oncogenes（Mst/Lats/Yap）could sense the changes of cell density in Drosophila ovary. Our prelimilary data in mice showed that Hippo component Yap had dramatic expression changes after initiation of primordial follicles. Thus, we hypothesize that Hippo signaling pathway may trigger the initiation of primordial follicles in mammals. In this project, utilizing mouse and human ovary samples, we will analyze the correlation between the expression levels of key molecules in the Hippo signaling pathway and the changes of the primordial follicle pools. At the same time, through genetically manipulating the Hippo pathway, the effects and related mechanisms of Hippo pathway regulation on the initiation of primordial follicle will be explored. Furthermore, the development potentiality and fertility of primordial follicles activated by Hippo pathways modulation will be investigated. The applicant has extended research experience in the field of primordial follicles development and maturation（Reprod Biol Endocrinol，2010；DNA and Cell Biology, 2012）, hoping the success of this project will provide valuable scientific basis for the diagosis and treatment of the related female reproductive disorders...