室性心律失常是心源型猝死的主要原因，严重危害人类健康。在细胞水平，氧化应激相关的心肌细胞早后除极（EADs）是室性心律失常发生的最重要的电生理机制之一。我们前期工作发现TRPM2通过影响RIP3/CaMKII信号参与心室肌细胞EADs的形成，但其分子调控机制仍知之甚少。本课题拟在细胞实验和转基因动物层面，利用膜片钳技术、分子生物学技术、基因编辑、植入式心电遥测等技术，系统研究：（1）明确TRPM2通道是否参与氧化应激相关的心室肌细胞EADs的形成；（2）阐明氧化应激RIP3/CaMKIIδ信号通路对TRPM2激活的调控作用及其机制；（3）利用心肌特异性敲除与过表达TRPM2动物建立心梗模型，进一步探讨TRPM2、EADs与室性心律失常发生的潜在关系。本项目实施不仅将丰富EADs离子通道学说，还将为室性心律失常的防治提供新的靶点。

Ventricular arrhythmia is a major cause of sudden cardiac death which poses a serious threat to human health. Oxidative Stress-related cardiac early afterdepolarizations (EADs) is one of the most important mechanisms of ventricular arrhythmia at the cellular level. Our preliminary data has found that TRPM2 channel activation contributes to H2O2-induced EADs formation in cardiomyocytes by affecting RIP3/CaMKIIδ signaling. However, the molecular mechanism underlying this process is far beyond understanding now. We hypothesize that TRPM2 might be involved in the formation of EADs caused by oxidative stress via RIP3/CaMKIIδ/TRPM2 pathway. To test the hypothesis, we will employ multiple techniques, including patch-clamp, molecular biology, cardiac telemetry system, transgenic mice, adenovirus-mediated knockdown and overexpression, et.al., to: (1) verify that TRPM2 involved in oxidative stress-related EADs in ventricular myocytes; (2) characterize the regulatory effect of RIP3/CaMKIIδ pathway on TRPM2 activation and its mechanism at the level of neonatal rat ventricular myocytes and adult rat ventricular myocytes; (3) investigate the potential relationship between TRPM2, EADs and ventricular arrhythmia in vivo by subjecting the wildtype (WT) and cardiac specific TRPM2 knock-out (KO) or over-expression (OE) rat to myocardial infarction. In summary, the study will extending our understanding of the ionic channel theory of EADs, and may provide a novel therapeutic target for improving the prevention and treatment of ventricular arrhythmia.