DMRTA1/RAGE调控肝脏胰岛素抵抗的分子机制

项目名称： DMRTA1/RAGE调控肝脏胰岛素抵抗的分子机制

项目编号： No.81500186

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： 聂少芳

作者单位： 华中科技大学

项目金额： 18万元

中文摘要： 冠心病和糖尿病血管病变的发生可能具有“共同土壤”。我们研究发现位于9p的多态性位点rs10757283可增加冠心病和糖尿病血管病变的发生风险，该遗传变异可调节基因DMRTA1的表达。DMRTA1是性别决定基因的一种，具有转录因子特性，在哺乳动物的肝脏、肾脏、胰腺中表达丰富。我们前期研究发现，高脂饮食可诱导小鼠肝脏发生脂肪变性，且伴随DMRTA1表达上调，提示DMRTA1可调控高脂饮食诱导的肝脏胰岛素抵抗。生物信息学和文献分析提示，DMRTA1可调控RAGE的表达，而后者可能通过影响IRS-2/PI3K/AKT信号通路来诱导肝脏胰岛素抵抗的发生和发展。因此，本课题拟建立胰岛素抵抗细胞模型和动物模型，从离体和在体两个层面探讨DMRTA1/RAGE信号通路调控肝脏胰岛素抵抗的分子机制，为冠心病和糖尿病血管病变的防治研究提供有效的生物学靶点。

中文关键词： DMRTA1；RAGE；胰岛素抵抗；冠心病；糖尿病

英文摘要： The vasculopathy incidence of coronary heart disease (CHD) and diabetes mellitus might have the common soil. Our study found that the variant rs10757283 in 9p could increase the risk of vasculopathy in CHD and diabetes mellitus, and regulate the expression of DMRTA1. DMRTA1 is a kind of sex determining genes, can function as a transcription factor, and is highly expressed in liver, kidney and pancreas of mammalian. Our previous study found that, high fat diet induced mouse liver fatty degeneration, and accompanied by the upregulation of DMRTA1 expression, which suggested that DMRTA1 could regulate the hepatic insulin resistance induced by high fat diet. Bioinformatics and literature analysis suggested that, DMRTA1 could regulate the expression of RAGE, and the latter might induce hepatic insulin resistance by influencing the IRS-2/PI3K/AKT signaling pathway. Therefore, this study intents to establish the cell and animal model of insulin resistance, and to explore the molecular mechanisms of DMRTA1/RAGE in the regulation of hepatic insulin resistance in vitro and in vivo, which might provide valuabe biologic target for the prevention and treatment of the vasculopathy in CHD and diabetes mellitus.

英文关键词： DMRTA1;RAGE;insulin resistance;coronary artery disease;diabetets mellitus