多囊卵巢综合征（PCOS）是育龄妇女最常见内分泌疾病，高雄激素血症是其核心表现。申请人围绕高雄激素的发病机制和临床治疗，研究成果包括：1)发现了11个PCOS遗传易感位点，其中DENND1A，YAP等基因参与高雄激素血症发病；2)在此基础上构建了风险预测模型用于临床；3)证明了棕色脂肪移植可改善高雄有效治疗PCOS。以上成果为PCOS发病和治疗提供了崭新思路，发表SCI论文40余篇，包括Nat Genet, Am J Hum Genet, PNAS等杂志。.课题组前期发现PCOS的新易感基因DENND1A在患者中表达增高，体外实验证实该基因可致雄激素增高，我们构建的Dennd1a转基因鼠恰可模拟人PCOS。在此基础上，本项目将研究DENND1A在雄激素合成、卵泡发育和PCOS发病中的作用以及分子调控机制，结合棕色脂肪移植，寻找药物治疗新靶点，为后期临床试验提供有力理论依据。

Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women of reproductive age, is primarily characterized by hyperandrogenemia. My research has been focused on the pathogeneses and treatments of PCOS, and our major achievements are as follows: 1) We identified 11 susceptibility loci for PCOS, in particular we found that genes such as DENND1A, YAP play important roles in the synthesis of androgen; 2) We constructed the first genetic risk prediction model for PCOS; 3) We provided evidence that brown adipose tissue (BAT) could reverse PCOS phenotype in a rat model. These findings represent significant contribution towards the understanding of PCOS and resulted in over 40 publications in peer-reviewed journals including Nat Genet, Am J Hum Genet, PNAS et al..Previous studies by our group have demonstrated that DENND1A is one of the susceptibility genes for PCOS. In patients with PCOS, DENND1A expression is increased, and is positively correlated with testosterone level. Furthermore, ovaries from transgenic Dennd1a mouse are characterized by PCO morphology. Thus, we postulate that DENND1A may play important roles in the regulation of androgen synthesis and folliculogenesis. We propose to: 1) explore the function of DENND1A in follicle growth using in-vitro follicle culture as well as DENND1A transgenic mouse model; 2) identify the mechanisms of action of DENND1A on androgen production, especially the role of the C/EBP Beta pathway; 3) fine-map the causal variants impacting DENND1A expression in PCOS patients; 4) transfer BAT to the transgenic Dennd1a mice to identify the detailed mechanism of BAT activity. Overall, we anticipate that this project will provide new findings pertinent to the pathogenesis and development of novel treatment of PCOS.