高胰岛素血症与高雄激素血症是PCOS的两大基本病理特征。临床研究显示高胰岛素血症可加重高雄激素血症。本课题组既往研究证实高胰岛素状态下miRNA是调控雄激素合成的关键分子，我们筛选和验证了miR-92a在伴有高胰岛素血症PCOS患者的卵巢组织中表达下调最明显，并证实miR-92a通过调控雄激素合成关键酶CYP17促进雄激素的合成，且该作用呈现胰岛素时间-剂量依赖性。为深入探讨胰岛素调控miR-92a的分子机制，本项目拟进一步采用高通量转录因子芯片筛选胰岛素刺激下调控miR-92a的转录因子，并通过EMSA、CHIP、BSP等方法获得转录因子调控miR-92a的直接证据，揭示胰岛素在转录和表观遗传学水平调控miR-92a表达，进而促进雄激素合成的分子机制；为阐明PCOS高胰岛素血症调控高雄激素血症内在作用关键因子，阻断其病理进程提供新线索；为临床治疗提供新思路，为发展新型基因治疗药物奠定基础

Insulin resistance /hyperinsulinemia and hyperandrogenism are key features of polycystic ovary syndrome (PCOS). Human studies have confirmed that insulin can increase circulating androgen levels in women with PCOS. Our previous study demonstrated that microRNAs play a pivotal role in regulating of androgen synthesis in PCOS patients with hyperinsulinemia. We found that expression of miR-92a was the most down-regulate microRNA in the PCOS with hyperinsulinemia, which promoted the androgen synthesis by targeting the cytochrome P450 17 (CYP17) protein. Furthermore, we found the expression of miR-92a was down-regulated by insulin in a time- and dose-dependent manner. In order to clarify the molecular mechanisms of insulin in the regulation of miR-92a expression, we plan to explore the transcript factors and their functional roles in differential microRNA expression. By using oligonucleotide array-based transcription factor assay, electrophoretic mobility shift assay, chromatin immunoprecipitation, and bisulfite sequencing PCR, we will shed light on the role of microRNA participating in insulin increase circulating androgen levels, and will provide a new insight of pathophysiology in PCOS and new target for therapies.