雄激素和炎症在颗粒细胞微环境中的交互作用对多囊卵巢综合征卵巢局部胰岛素抵抗的影响

项目名称： 雄激素和炎症在颗粒细胞微环境中的交互作用对多囊卵巢综合征卵巢局部胰岛素抵抗的影响

项目编号： No.81471429

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刁飞扬

作者单位： 南京医科大学

项目金额： 73万元

中文摘要： PCOS患者临床有很多亚型，70%合并肥胖，10%的瘦型和50%的肥胖型患者伴有外周胰岛素抵抗，而瘦型LH和雄激素更高。高雄激素合并月经稀发的PCOS亚群是发生代谢综合征的高危人群。慢性低剂量炎症是糖尿病和心血管疾病的危险因素，外周炎症因子与肥胖呈正相关。说明慢性炎症和高雄激素都可能和糖脂代谢异常有关。本课题组既往研究显示NR4A1基因在小鼠卵巢颗粒细胞中通过IRS-1/AKT/GLUT4通路促进葡萄糖摄取，其在PCOS患者卵巢内表达下调是局部胰岛素抵抗的机制之一，更让人感兴趣的是还发现NR4A1在小鼠颗粒细胞内参与调控雄激素合成和炎症因子TNF-α的表达变化。我们希望通过对瘦型/胖型PCOS患者、小鼠颗粒细胞原代培养体系、Nr4a1基因敲除小鼠的研究，找到颗粒细胞局部微环境中雄激素-慢性炎症交互作用导致胰岛素抵抗的机制，特别是NR4A1在其中的重要作用，为临床分型而治提供理论依据。

中文关键词： 胰岛素抵抗；高雄激素血症；慢性炎症；颗粒细胞；多囊卵巢综合征

英文摘要： PCOS patients have complicated subtypes, 70% with obesity, and peripheral insulin resistance appeare in 50% of obese and 10% lean patients, as the latter have higher LH and androgen level. Subgroup of PCOS with hyperandrogenism and oligomenorrhea are at high risk of metabolic syndrome. Chronic low-dose inflammation is a risk factor for diabetes and cardiovascular disease. Level of peripheral inflammatory factors was positively correlated with obesity. Chronic inflammation and hyperandrogenism may induce glucose and lipid metabolism abnormalities. Our published studies have revealed that NR4A1 gene promoted glucose uptake in mouse ovarian granulosa cells via IRS-1/AKT/GLUT4 pathway. The lower expression in PCOS patients ovary may be one of the mechanisms of ovarian insulin resistance. The most interesting thing was that NR4A1 regulated androgen synthesis and has the relation with inflammatory cytokines TNF-α in mice granulosa cells. We want to study the interaction of androgen and chronic inflammation in granulosa cell microenvironment using the lean / fat subtype of PCOS patients, primary cultured mouse granulosa cells, and Nr4a1 knockout mice. We supposed that this kind of interaction can lead to the insulin resistance in granulose cells, and in particular, NR4A1 may play important role in it. We also hope this study can provide important clues for Individualized therapy strategy for different subtype PCOS patients.

英文关键词： insulin resistance;hyperandrogenism;chronic inflammation;granulosa cell;polycystic ovary syndrome