RBP4通过自噬-NLRP3炎性小体途径促进糖尿病心肌损伤的机制研究

项目名称： RBP4通过自噬-NLRP3炎性小体途径促进糖尿病心肌损伤的机制研究

项目编号： No.81470501

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： 鲁翔

作者单位： 南京医科大学

项目金额： 73万元

中文摘要： 糖尿病心肌病（DCM）是2型糖尿病患者心力衰竭的主要原因，炎症反应是导致DCM的重要机制之一，其中心肌NLRP3炎性小体的活化至关重要。研究表明过度自噬可通过激活NLRP3炎性小体促进炎症反应,而2型糖尿病心肌自噬被过度激活。视黄醇结合蛋白4（RBP4）是新的促炎症因子，我们前期发现RBP4升高可促进胰岛素抵抗，导致2型糖尿病,并发现血清RBP4水平在DCM中升高，且RBP4刺激可激活心肌细胞自噬。据此提出科学假说：2型糖尿病时RBP4升高诱导心肌细胞过度自噬，激活NLRP3炎性小体，促进心肌炎症反应，从而导致糖尿病心肌损伤。本项目将在心肌细胞确证RBP4通过诱导过度自噬激活NLRP3炎性小体的作用及机制；并在细胞水平干预RBP4表达,分析其对高糖诱导的心肌细胞炎症损伤的影响；在RBP4转基因和敲除鼠2型糖尿病模型中，研究干预RBP4表达对DCM进程的影响，为DCM防治提供新思路和新靶点。

中文关键词： 糖尿病心肌病；视黄醇结合蛋白4；NLRP3炎性小体；自噬；心肌细胞

英文摘要： Diabetic cardiomyopathy (DCM) is a major cause of heart failure in patients with type 2 diabetes (T2D). Inflammation is one of the most important pathogenic factors contributing to DCM. Activation of NLRP3 inflammasome plays a crucial role in the inflammatory process of diabetic myocardium. NLRP3 inflammasome can be activated by excess autophagy, which is common in T2D. Recent studies showed that retinol binding protein 4 (RBP4) is a novel proinflammatory factor. Our previous studies have demonstrated that RBP4 could cause insulin resistance and T2D, and serum levels of RBP4 were increased in mice with DCM. In cultured cardiomyocytes, stimulation with human recombinant RBP4 upregulated the level of autophagy. Thus we hypothesized that In T2D, upregulated RBP4 may induce excess myocardial autophagy, which in turn promotes the activation of NLRP3 inflammasome, and will subsequently cause diabetic myocardial injury. In the present study, we will firstly determine the molecular mechanism by which RBP4 induces excess autophagy and whether RBP4 induced excess autophagy activates NLRP3 inflammasome in cardiomyocyte. And then we will investigate whether upregulated RBP4 promotes diabetic myocardial injury via autophagy-NLRP3 inflammasome pathway in high glucose-induced cardiomyocyte model as well as in RBP4 transgenic and knockout T2D mice models. This proposal will provide a new insight into prevention and treatment for DCM.

英文关键词： diabetic cardiomyopathy;retinol binding protein 4;NLRP3 inflammasome;autophagy;cardiomyocyte