引起糖尿病心肌重构的机制尚未完全阐明，目前仍无有效手段抑制糖尿病心肌病发生发展。线粒体动力学稳定是维持心脏功能的前提，糖尿病心肌组织线粒体分裂增加。Drp1磷酸化修饰是线粒体分裂的重要调控方式，并受多种因素调控。我们在前期研究中采用STZ诱导大鼠糖尿病，发现心肌组织中Drp1表达及Drp1（Ser616）磷酸化均增加。此外另一项研究提示糖尿病大鼠心肌微血管内皮细胞RhoA/ROCK通路激活，促进氧化应激反应，引起糖尿病心功能异常。基于此，本课题拟从线粒体动力学的角度，以“ROCK-Drp1信号通路”为靶点，分别从整体动物、组织和细胞水平探讨糖尿病心肌损伤及心室重构的分子调控机制，重点阐明RhoA/ROCK调控Drp1磷酸化在其中的作用，并通过ROCK抑制剂及基因修饰的方式在体验证RhoA/ROCK/Drp1信号通路对糖尿病心肌病的调控作用，为防治糖尿病心肌损伤及心室重构提供新靶点和新策略。

Diabetes mellitus (DM), a common metabolic disease related to many chronic complications, causes great challenge to public health all over the world. Diabetic cardiomyopathy (DCM) is a clinical condition of cardiac dysfunction, independently of hypertension, coronary artery disease and cardiac valvulopathy. DCM is a major risk factor for ill-health among diabetic population and responsible for increased morbidity and mortality. However, there is no effective treatment to prevent cardiac remodeling in DCM at present. Accumulating evidence has demonstrated that mitochondrial dynamics (mitochondrial fusion and mitochondrial fission) played a key role in DCM, which was one of the major components in triggering myocardial changes. Previous evidence showed increased mitochondrial fission in myocardium of DCM, which subsequently induced reactive oxygen species (ROS) generation, apoptosis, and myocardial collagen deposition. Phosphorylation was one of the major post-translational modifications for Drp1, which regulated mitochondrial fission. In the preliminary experiment, DCM was induced by STZ injection, and the protein levels of Drp1 and p-Drp1 (Ser616) were increased in myocardial tissue compared with control group. In addition, another study from our group showed that RhoA/ROCK pathway were activated in high glucose induced cardiac microvascular endothelial cells, which resulted in oxidative stress and cardiac dysfunction. Therefore, in the present study we are going to investigate whether RhoA/ROCK/Drp1 signal pathway mediates mitochondrial fission, and links to myocardial fibrosis and cardiac remodeling in diabetic cardiomyopathy.