Cav3抑制DRP1介导的线粒体分裂在糖尿病心肌病中的机制研究

糖尿病心肌病（DCM)常导致严重心衰，其发病机制不清。心脏高度耗能和依赖线粒体，近年研究认为代谢改变和线粒体分裂是DCM的发病基础，而DRP1是线粒体分裂的重要调控环节，糖尿病如何通过细胞膜传递信号导致线粒体分裂？小窝蛋白3（Cav3）是心肌上的细胞膜微囊关键成分和重要信号枢纽，我们早期的研究数据、近年的预实验提示，糖尿病小鼠心肌Cav3下调，而Cav3上调明显改善DCM线粒体的分裂。Cav3是否通过DRP1影响线粒体分裂导致心肌病? 其关键环节是Cav3-RCAN1-DRP1(p-637)或者DRP1(p-616）？对此国内外无相关报告，我们的近期研究显示，Cav3过表达可以上调RCAN1和DRP1(p-637)。本项目将在细胞及动物水平，利用基因突变、基因沉默及过表达Cav3，探讨上述关键通路的作用、机制及对心功能的影响，研究结果将为DCM防治策略提供新的思路。

Diabetic cardiomyopathy, one of the main causes of heart failure, presents poor therapeutic outcomes and possesses high mortality. However, the pathogenesis of diabetic cardiomyopathy is still unclear. Studies revealed that a heart is an energy-metabolic organ and highly relies on chondriosome. Mitochondrial fission secondary to metabolic changes, and then loss of function, has been gradually known as principal mechanism of developing diabetic cardiomyopathy. Additionally, DRP1 is critical in regulating mitochondrial fission How can diabetes mellitus transduce the signal and lead to mitochondrial fission via cell membrane? Caveolin 3 (Cav3), the cardiomyocyte-specific caveolar protein isoform, is critical in signal transduction on cell membrane. Our data from early NSFC program and recent pilot study demonstrated that Cav3 was down-regulated in diabetic cardiomyopathy in mice model, and its up-regulation can significantly ameliorate myocardial mitochondrial fission. Thus, does DRP1 mediate the effect of Cav3 down-regulation on diabetic cardiomyocyte and what is the mechanism? which is the principal pathway, Cav3-RCAN1-CaN-DRP1(p-Ser637) or DRP1(p-Ser616)? There is no report concerning those issues. Our recent study showed that over-expression of Cav3 could upregulate RCAN1 and DRP1(p-Ser637), the latter two can apparently inhibit mitochondrial damage. This program aims to explore the effect of Cav3 on DRP1 protein and its regulatory function by gene mutation, gene silencing, and over-expression at the cellular level and animal level, respectively, and elucidate the relationship between Cav3, RCAN1, and the different phosphorylation sites of DRP1. We plan to explore the effects of exogenous replenishing of Cav3 on cardiomyocyte apoptosis, oxidative stress, and cardiac function in diabetic cardiomyopathy, and to further investigate the role of RCAN1 during the course. The results will provide further insights in the pathogenesis of diabetic cardiomyopathy and provide a potential new strategy for the therapy of diabetic cardiomyopathy.