Humanin在多囊卵巢综合征卵巢局部胰岛素抵抗发生中的作用及机制研究

PCOS的发病机制不明，由IRS/PI3-K/AKT通路介导的胰岛素抵抗（IR）是其重要的病理特点。Humanin（HN）是一种线粒体基因编码的多肽，我们前期首次发现其在卵巢组织中高表达，在PCOS患者颗粒细胞及PCOS大鼠卵巢组织中表达均下调，补充外源性HN能够显著提升颗粒细胞葡萄糖代谢能力，上调IRS-1及AKT的表达并增加其磷酸化水平。因此，我们推测HN可能对PCOS IR的发生发展具有重要的调控作用，且可能是通过调控IRS/PI3-K/AKT通路实现的。本研究拟在前期研究基础上，综合利用人卵巢原代颗粒细胞、颗粒细胞系以及PCOS大鼠模型，深入探究HN在PCOS IR发生发展中的作用；验证HN是否通过调控IRS/PI3-K/AKT通路发挥对卵巢细胞糖代谢的调节作用；并试图找到HN的相互作用蛋白并探索其调控方式，以丰富对PCOS发病机制的认识，并为其临床治疗提供新的靶点和思路。

The pathogenesis of polycystic ovary syndrome (PCOS) is still largely unclear, and insulin resistance (IR) mediated by the IRS/PI3-K/AKT pathway is regarded as a main pathological characteristic. Humanin (HN) is a polypeptide encoded by mitochondrial gene, our previous study showed for the first time that HN was strongly expressed in human and rat ovaries. The expression of HN in granulosa cells from PCOS patients and rat models was significantly down-regulated, whereas supplementation of exogenous HN significantly improved glucose metabolism of granulosa cells, and up-regulated the expression of Insulin Receptor Substrate 1 (IRS-1) and AKT (protein kinase B), as well as increased the phosphorylation levels of these proteins. Therefore, we propose the hypothesis that HN plays an important role in the pathogenesis of IR in PCOS, and this may be mediated by IRS/PI3-K/AKT pathway. In this present study, we aim to further investigate the role of HN in the pathogenesis of IR of PCOS, to demonstrate whether the regulative effect of HN on ovarian cells is mediated by IRS/PI3-K/AKT pathway, and to identify the target protein of HN by which IRS/PI3-K/AKT pathway is regulated. Primary granulosa cells, immortalized human granulosa cells (SVOG cells) and PCOS rat models will be applied in this project. The results of this study will help better clarify the pathogenesis of PCOS, and provide new targets and ideas for the treatment of PCOS.