组蛋白甲基化酶G9a调控胰岛素受体及血糖水平的机制研究

项目名称： 组蛋白甲基化酶G9a调控胰岛素受体及血糖水平的机制研究

项目编号： No.31471208

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 黄昆

作者单位： 华中科技大学

项目金额： 80万元

中文摘要： 胰岛素受体（IR）在维持血糖平衡中举足轻重，其表达水平与糖尿病发生发展关系密切，但其表达调控机制仍不明确。申请人前期发现调控表观遗传修饰的重要组蛋白甲基化酶G9a能显著调控肝细胞IR水平及胰岛素信号通路，并在整体动物水平上直接影响血糖，提示了一个全新的IR表达调控机制。申请人还利用基因芯片技术发现G9a正向调节HMGA1和beta-arrestin-2基因。据此，本申请计划在细胞水平探索G9a对IR及胰岛素信号通路的调控是否依赖甲基化酶活性，验证HMGA1和beta-arrestin-2在该调控中所起作用；通过肝脏过表达或敲除G9a，在动物水平探索G9a对正常和2型糖尿病小鼠IR、胰岛素信号通路、HMGA1、beta-arrestin-2水平和血糖水平的影响。本项目有望揭示G9a调控IR水平及胰岛素信号通路并最终调控机体血糖水平的分子机制，为糖尿病预防和治疗提供新理论支持和药物干预新靶点。

中文关键词： 表观遗传学；组蛋白甲基化酶；胰岛素受体；2型糖尿病

英文摘要： Insulin receptor (IR) plays a critical role in the regulation of glucose homeostasis, its level is closely associated with the pathogenesis of diabetes and its complications. However, the exact molecular mechanisms underlying the IR regulation remain unclear. In pilot studies, the applicant found for the first time, that an important histone methyltranferase, G9a, which is essential in epigenetic modifications, significantly regulates the level of IR and the down-stream signal transduction pathway of IR. More importantly, G9a also regulates the level of blood glucose in vivo. All of these results implicate a new regulation mechanism in IR expression and blood glucose level. By using microarray technology, we further identified two G9a positively regulated genes, HMGA1 and beta-arrestin-2. In the present application, we propose to conduct research both in cell and in animal models. In cell models, we seek to investigate whether the methyltranferase activity of G9a is required for its regulation on IR and the downstream signal pathways of IR. The roles of HMGA1 and beta-arrestin-2 in these regulations will also be studied. By constructing G9a liver-specific over-expression or knockdown mice, we will further explore how G9a affects the levels of IR and its pathway, levels of HMGA1, beta-arrestin-2 and blood glucose. The research outcome of this proposal may reveal the mechanism of G9a action in regulating IR and its pathways, therefore may provide new insights into the prevention and treatment of diabetes.

英文关键词： epigenetics;histone methyltransferase;insulin receptor;type 2 diabetes