组蛋白甲基化酶G9a调控糖尿病肾病中巨噬细胞极化失衡的机制研究

项目名称： 组蛋白甲基化酶G9a调控糖尿病肾病中巨噬细胞极化失衡的机制研究

项目编号： No.81500634

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 黄进

作者单位： 华中科技大学

项目金额： 18万元

中文摘要： 不同亚型巨噬细胞的极化在糖尿病肾病（DN）中扮演着重要作用。M1/M2型巨噬细胞的极化失衡是DN的潜在致病机制，但其分子机制尚不清楚。高血糖是诱导肾脏巨噬细胞极化失衡的重要因素，申请者前期工作发现组蛋白甲基化酶G9a在M2型巨噬细胞极化过程中表达降低，高糖刺激则促进G9a的表达；提示G9a可能调控DN中巨噬细胞的极化。本课题拟通过链脲佐菌素诱导的糖尿病小鼠模型，研究DN中巨噬细胞的极化失衡和G9a在不同亚型巨噬细胞中的定位和表达情况；采用体外巨噬细胞诱导极化模型，研究高血糖诱导的巨噬细胞极化失衡，探索G9a在高血糖调控M2型巨噬细胞极化中的介导作用，阐明G9a对M2型巨噬细胞极化关键因子PPARγ的调控机制；同时，利用巨噬细胞特异过表达G9a的转基因小鼠，体内研究G9a介导DN中巨噬细胞极化失衡的作用和分子机制，探讨其在DN发展中的作用。本课题将阐明DN中巨噬细胞极化失衡的新的调控机制。

中文关键词： 糖尿病肾病；巨噬细胞极化；G9a；PPARγ

英文摘要： Distinct subtypes macrophage polarization plays an essential role in diabetic nephropathy (DN). M1/M2 macrophage polarization imbalance is an potential mechanism in the pathogenesis of DN, but the molecular mechanisms are still unclear. Hyperglycemia is the major factor in renal macrophage polarization imbalance, the applicant previously found that histone methyltransferase G9a was decreased in the process of M2 macrophage polarization, and high glucose treatment improved G9a expression.These observations suggest that G9a maybe involved in the regulation of macrophage polarization in diabetic nephropathy. In this study, we will use the streptozotocin-induced diabetic mice to investigate the macrophage polarization imbalance in diabetic nephropathy and the localization and expression of G9a in different macrophage subtypes. Via inducing macrophage polarization in vitro, we will study the macrophage polarization imbalance induced by hyperglycemia, explore the role of G9a in mediating hyperglycemia-regulated M2 macrophage polarization, and demonstrate the mechanisms of G9a in regulating PPARγ which is the key factor to control M2 macrophage polarization. Meanwhile, by means of macrophage specific G9a transgenic mice, we will investigate the role and molecular mechanisms of G9a in mediating macrophage polarization imbalance in diabetic nephropathy, and explore the role of G9a in the development of diabetic nephropathy in vivo. This study will demonstrate a novel regulatory mechanism of macrophage polarization imbalance in diabetic nephropathy.

英文关键词： diabetic nephropathy;macrophage polarization;G9a ;PPARγ