DACH1苏木化修饰减退在糖尿病心肌损伤中的作用及机制研究

糖尿病心肌损伤是影响患者预后的重要临床问题，发病机制不明且缺乏有效干预手段。申请者曾证实DACH1是决定细胞命运的重要转录因子（PNAS，JBC 2010）。新近流行病学证据显示DACH1与糖尿病和心脏疾病密切相关，但其是否参与糖尿病心肌损伤尚未阐明。我们前期研究发现糖尿病心肌中DACH1表达升高激活内质网应激和细胞凋亡。而DACH1表达升高可能与CaMKII抑制其苏木化修饰有关。推测糖尿病状态下DACH1的苏木化修饰被CaMKII抑制后激活内质网应激诱导心肌细胞凋亡。提示DACH1苏木化修饰是研究糖尿病心肌损伤的新靶点。干预DACH1苏木化修饰可能是抑制糖尿病心肌损伤的新手段。本项目以DACH1苏木化修饰为核心，利用动物、组织、细胞和分子采用多种研究手段明确其在糖尿病心肌损伤中的作用，阐明损伤机制，观察干预效果并揭示DACH1苏木化修饰的分子机制，为防治糖尿病心肌损伤提供新理论和新策略。

Diabetic myocardial injury is a critical clinical issue for the diabetic patients and has a significant impact on patients’ prognosis. However, the underlying mechanisms of diabetic myocardial injury are still unclear and effective treatment is urgently needed. The applicant of this project has confirmed that DACH1 is an important transcription factor determining cell fates (PNAS, JBC 2010). Recent epidemiological data suggested that DACH1 played important roles in diabetes and cardiovascular diseases. Whether DACH1 is involved in the development of diabetic myocardial injury is need to be elucidated. Our pilot studies showed that DACH1 expression was upregulated in cardiomyocytes of diabetic mice, and DACH1 overexpression promoted ER stress and cell apoptosis of diabetic cardiomyocytes. Upregulation of DACH1 expression was found to be related with reduced SUMOylation which was inhibited by Ca2+/calmodulin-dependent protein kinase II（CaMKII）. We hypothesized that in diabetic cardiomyocytes, DACH1 SUMOylation downregulated by CaMKII induced ER stress, cell apoptosis, and eventually resulted in myocardial injury. Our findings identified DACH1 as a novel target for diabetic myocardial injury. The interventions on DACH1 SUMOylation will be potential new strategies for the disease. The present project will focus on DACH1 SUMOylation and investigate its roles in diabetic myocardial injury. We will clarify the mechanisms of DACH1 induced diabetic myocardial injury and determine the effects of DACH1 SUMOylation intervention on diabetic myocardial injury, as well as elucidating the molecular mechanisms of DACH1 SUMOylation. The findings of our study will provide further insights and new invention strategies for clinical treatments of diabetic myocardial injury.