多囊卵巢综合征（PCOS）发病率高，可致生殖障碍及代谢异常，严重危害女性健康，增加医疗负担，其发病机制尚未阐明。本课题组前期通过转录组测序构建了PCOS患者颗粒细胞mRNA及lncRNA差异表达谱，发现与AMH信号通路密切相关的lncRNA Malat1与PCOS发病之间存在关联。本研究拟进一步采用Malat1基因敲入小鼠模型、Malat1过表达/敲减细胞模型，观察生殖内分泌/卵子发育表型、细胞增殖/凋亡、甾体激素调节关键分子，阐明Malat1表达异常致PCOS发病的效应。通过AMH与Malat1关联分析，RNA免疫共沉淀、染色质免疫共沉淀、荧光素酶报告基因、siRNA等技术探索AMH调节 Malat1表达、参与PCOS发病的关键步骤及调控因子，明确Malat1介导AMH在PCOS发生发展中的作用及精细调节网络，为PCOS的临床筛查与靶向干预提供理论基础，兼具重大科研价值和转化医学意义。

Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders and a leading cause of female infertility and abnormal metabolism, and is significantly related to negative female health effects and increased social medical cost. The mechanism underlying the pathophysiology of PCOS remains to be illustrated. In our previous studies, we successfully constructed a differently expressed RNA transcriptome profile which includes long non–coding RNAs (lncRNA) and mRNAs in granulose cells (GCs) of PCOS patients compared with control via RNA sequence. We found that Malat1, which is involved in AMH signal transduction, is one of the differently expressed lncRNA in GCs of PCOS patient. Based on the previous results, we plan to further clarify Malat1-mediated effects and molecular mechanisms of AMH in the development of PCOS, by constructing mouse/cell model with Malat1 knock-in and cell model with Malat1 knock-down. The reproductive phenotype including reproductive endocrinology, oogenesis of the animal model and proliferation/apoptosis/steriogenesis of cell models will be analyzed to confirm whether dis-regulated Malat1 will impaire oogenesis and steroidogenesis similar with PCOS. A series of experiments by RNA immunoprecipitation , real-time PCR, Western-blot , siRNA transduction and chromatin immunoprecipitation will be employed to explore the effects and mechanisms of AMH in up-regulating Malat1, and to figure out the crucial steps, the key regulatory factors and the precise regulatory network of AMH and Malat1 in PCOS development. The expected results will provide valuable theoretical basis for early screening and interference of PCOS, which will contribute to improving female reproductive health, and reducing related health-care costs.