Parkin/DJ-1调控的线粒体自噬在恢复糖尿病心肌对缺血后处理敏感性中的作用及机制

项目名称： Parkin/DJ-1调控的线粒体自噬在恢复糖尿病心肌对缺血后处理敏感性中的作用及机制

项目编号： No.81471844

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： 夏中元

作者单位： 武汉大学

项目金额： 72万元

中文摘要： 糖尿病患者心脏较非糖尿病患者更不易耐受缺血/再灌注损伤(IRI),且对缺血后处理（IPO）的敏感性降低,我们前期研究发现其与线粒体自噬功能紊乱有关，但其具体调控机制仍然未明。新近研究表明Parkin与DJ-1是调控线粒体自噬的关键因子。我们预实验表明, 糖尿病心肌Parkin与DJ-1虽可形成蛋白复合体但两者的表达水平显著降低,应用自噬诱导剂可抑制糖尿病心肌IRI并可恢复糖尿病心肌对IPO的敏感性。据此，我们推测Parkin/DJ-1调控的线粒体自噬是糖尿病心肌抗IRI并恢复对IPO敏感性的关键途径。本项目拟用特异性基因敲除小鼠、原代心肌细胞为研究对象，探讨Parkin/DJ-1调控的线粒体自噬在恢复IPO对糖尿病心肌保护中的作用及分子机制, 并观察其对线粒体自噬信号通路AMPK/Akt/TSC/mTOR的影响，以期为临床开发糖尿病心肌IRI保护药物或措施提供实验依据。

中文关键词： Parkin；DJ-1；线粒体自噬；缺血后处理；糖尿病

英文摘要： Diabetic patients are more vulnerable to myocardial ischemia reperfusion injury (IRI),but less or not responsive to therapeutic interventions such as ischemic postconditioning (IPO) as compared with non-diabetics. Our previous study showed this was associated with mitophagy dysfunction, but its underlying mechenisms are still unknown.Recent studies indicated that Parkin and DJ-1 were the key factor regulating mitophagy.In our preliminary study, the protein complex of Parkin and DJ-1 was found in diabetic myocardium,though their expression was significantly downregulated, and autophagy inducers could inhibit myocardial IRI and restore the sensitivity to IPO in the diabetic myocardium. Therefore, we hypothesize that Parkin/DJ-1 regulated mitophagy is the key way to reduce IRI and restore the sensitivity of IPO in diabetic myocardium.In the current proposal, we will use the selective gene knockout mice and primary cultured cardiomyocytes to make diabetic model or high glucose with hypoxia/reoxygenation model, to elucidate the roles and mechanisms of Parkin/DJ-1 regulated mitophagy restoring IPO senstivity to diabetic myocardium, and invetigate its effects on the mitophagy sigaling pathway, such as AMPK/Akt/TSC/mTOR. This proposed studies will improve our understanding of diabetic myocardial IRI and may help facilitate the development of novel and optimal therapies in diabetic and ischemic heart disease.

英文关键词： Parkin;DJ-1;mitophagy;ischemic postconditioning;diabetes