KChIP2是心脏瞬间外向钾电流Ito的必须b亚基，对其功能起不可或缺的调节作用。KChIP2还决定Ito的发育变化特性和在心室壁的跨壁梯度，对维持心脏电稳态至关重要。多种心脏疾病通过降低KChIP2蛋白表达而抑制Ito电流，引起心律失常。但KChIP2的生理和病理调节机制尚待查明。MG53是心肌和骨骼肌特异表达的TRIM家族成员，我们前期工作发现，过表达MG53增加心肌细胞KChIP2蛋白和Ito电流,降低MG53表达则起相反作用，表明MG53是心脏内在的KChIP2调节分子。据此，本项目拟开展以下研究：1.MG53调节KChIP2表达的机制是什么？2.MG53在KChIP2和Ito发育变化中的作用？3.MG53对也受KChIP2调节的L-型钙通道和IK,slow的调节作用？4.MG53在心肌梗死心电紊乱发生中的作用及治疗意义？以此阐明心脏电稳态调节的新机制，探寻心律失常治疗的新靶点。

KChIP2 is the obligatory beta subunit of cardiac transient outward current (Ito), which is essential for regulating Ito function. KChIP2 protein levels increase with the development of heart, which determines the developmental increase of cardiac Ito. Furthermore, the transmural gradients of KChIP2 transcription across the free ventricular wall (epicardial myocytes > mid- cardial myocytes > endocardial myocytes) in many species contribute to the Ito transmural grandients which are critical determinants of myocardial function. In multiple heart diseases, such as hypertrophy, infarct cardiomyopathy, heart failure, etc, Ito amplitudes are consistently decreased, predisposing the heart to the risk of ventricular arrhythmia. A series of studies demonstrate that decrease in KChIP2 protein expression is an important mechanism for the downregulation of Ito in diseased hearts. Therefore, KChIP2 plays an important role in maintaining cardiac electrical stability. Unfortunately, the mechanisms underlying physiological and pathological regulation of KChIP2 expression and Ito function are largely unknown. MG53 is a member of TRIM family, which is specifically expressed in myocardium and skeletal muscle. Our preliminary data demonstrate that adenoviral overexpression of MG53 increased KChIP2 protein levels in cardiomyocytes, whereas MG53 knockdown by RNA interference decreased KChIP2 protein expression. Concomitantly, MG53 overexpression in cardiomyocytes increased the amplitude of Ito, while MG53 knockdown decreased cardiac Ito. These findings implicate that MG53 is an intrinsic regulator of KChIP2 expression in the heart. Based on the findings, we intend to address the following important questions in this project. First, what are the molecular mechanisms underlying MG53 regulation of KChIP2 expression in cardiomyocytes. Second, what is the role of MG53 in the developmental increase of KChIP2 expression and Ito function, and what are the underlying mechanisms. Third, whether and how MG53 regulates L-type Ca2+ current and IK,slow which have been suggested to be regulated by KChIP2 in cardiomyocytes. Furthermore, we will explore the alteration of MG53 in infarct cardiomyopathy and its role in the pathogenesis of electrical disturbances which are related to downregulation of Ito due to the decrease of KChIP2 expression. The potential therapeutic effect of modulating MG53 expression on the treatment of arrhythmia in diseased hearts will also be investigated in this project. Through these efforts, we hope to uncover novel mechanisms participating in maintaining cardiac stability and new therapeutic targets for the treatment of arrhythmia in heart diseases.