糖尿病心肌病（DCM）是由糖代谢异常所致的一种心脏病，表现为心肌舒缩功能受损和心肌重构。高迁移率族蛋白B1（HMGB1）在DCM时明显升高并与DCM的发生发展密切相关，其机制尚待阐明。我们以往工作发现HMGB1增加肌浆网（SR）ryanodine receptor活性。在此，我们提出以下设想：DCM时增加的HMGB1通过引起SR钙漏流造成（1）心肌收缩力降低；（2）心肌肥大性改变；（3）心脏纤维化重构，从而引起糖尿病心肌病发生。抑制SR钙漏流可抑制HMGB1引起的糖尿病心肌病的发生。本项目拟利用分子生物学、confocal钙显微成像、DCM动物模型等技术查明HMGB1-介导的SR钙漏流在DCM中的作用和机制。还将探讨抑制SR钙漏流药物（JTV519）对DCM的治疗作用。旨在阐明DCM发生的机制，为治疗提供新思路。

Diabetic cardiomyopathy (DCM) is a kind of heart disease caused by abnormal glucose metabolism, which is manifested as cardiac systolic and diastolic dysfunction and myocardial remodeling, including cardiac hypertrophy and fibrosis. It is well established that High mobility group protein B1 (HMGB1) increases significantly in DCM and is closely related to the development of DCM. However the underlying mechanisms remains largely unknown. Our previous work demonstrated that HMGB1 increased the activity of ryanodine receptors (RyRs) in sarcoplasmic reticulum (SR), leading to enhancement of SR Ca2+ leakage. A recent research has link SR Ca2+ leak to cardiac remodeling in ischemic-reperfusion heart injury. Therefore, we proposed that SR Ca2+ leakage contributed to decreased myocardial contractility, myocardial hypertrophy and cardiac fibrotic remodeling induced by increased HMGB1 in DCM. We will apply multiple advanced technologies, such as manipulation of gene expression, confocal Ca2+ imaging of local Ca2+ signal (Ca2+ sparks) in cardiomyocytes and producing DCM animal model, to testify our hypothesis and investigate the possible underlying mechanisms. Furthermore, we will explore the therapeutic effect of inhibition of SR calcium leakage with RyR stabilizer, JTV519, on the treatment of diabetic cardiomyopathy induced by HMGB1. Through these efforts, we hope to enrich our understanding of the mechanism of DCM and provide new therapeutic strategies for the treatment of DCM.