心肌缺血再灌注（MI/R）合并2型糖尿病（T2D）明显增加冠心病患者死亡率。研究表明，自噬在MI/R时起保护作用；合并T2D时，心肌细胞自噬降低，其保护作用减弱。研究证实，SIRT1调控FOXO去乙酰化激活，从而促进心肌细胞自噬。我们发现，T2D MI/R动物模型SIRT1介导的自噬信号通路受抑制，这一调控机制尚未阐明。研究证明，乳腺癌敲除基因1（DBC1）下调SIRT1的功能。我们发现，炎症可上调DBC1表达，后者可激活炎症反应，加重炎性损伤。因此推测，T2D上调DBC1表达，在MI/R时抑制SIRT1信号介导的自噬作用，从而加重心肌损伤。本课题将建立DBC1敲除小鼠MI/R T2D模型，分子免疫学方法检测心肌细胞自噬水平，组织学和影像学评价心肌损伤。结合体内外实验探究T2D上调DBC1表达，进而抑制MI/R时心肌细胞自噬的作用及机制，为临床保护MI/R T2D心肌损伤提供新的治疗思路

Myocardial ischemia reperfusion (MI/R) combined with type 2 diabetes (T2D) significantly increased the mortality of patients with coronary heart disease. Studies have shown that autophagy plays protective role in I/R injury.While, autophagy is inhibited, and its protective role is restrained during MI/R combined with T2D. Recent studies confirmed that SIRT1 up-regulate the acetylation of FOXO, thereby promoting its activation and cardiomyocyte autophagy.We found that, SIRT1 signaling was inhibited during MI/R combined T2D. However, the exact mechanism has not yet been elucidated. Research proves that delected in breast cancer 1 (DBC1) can suppress the acetylation function of SIRT1. We also found that inflammation increased expression of DBC1, which can be activate inflammation, aggravating inflammatory injury in return. We speculate that T2D increase DBC1 expression at the time of MI/R, thus aggravate myocardial injury via inhibition of autophagy mediated by SIRT1 signaling. To prove the hypothesis, we will firstly establish MI/R T2D model on DBC1 knockout mice, and evaluate the cardiomyocytes autophagy level through molecular immunology way, and detected the myocardial injury by histological and radiographic method. Combination of in vitro and in vivo experiments, we will explore the effect and mechanism of how T2D increase DBC1 expression, thereby inhibiting the myocardial cell autophagy during MI/R injury. This project would provide new evidence for the therapy and intervention of myocardial injury of MI/R T2D.