LQTS是常见心脏离子通道病之一。HERG蛋白编码的Ikr异常是LQT2的主要发病原因。HERG通道上游细胞器的内质网应激( ERS)在离子通道功能的调控有重要作用，但具体机制尚无系统研究。课题组前期发现在突变细胞中，内质网相关分子伴侣升高，而药物恢复突变蛋白的转运。但ERS通过何种途径作用突变蛋白，药物干预不同突变位点是否有区别未深入探讨。本课题拟以A561V和E637K突变基因为研究对象，在细胞水平上运用分子生物学及电生理学方法，探讨ERS在HERG突变蛋白转运中具体调控作用；并采用ERS相关药物干预，探讨其对及ERS和蛋白质转运障碍的影响。总之本课题拟多角度探讨ERS在HERG突变蛋白转运中的调控机制；并调控ERS来改善HERG蛋白功能。该研究将有助于探讨心脏离子通道功能异常发生机制，并为寻找新的心律失常干预靶点提供新的切入点和理论依据。

Long QT syndrome(LQTS) is a common cardiac channelopathy.Blocked or reduction of Ikr conducted by HERG proteins is the main cause of LQT2.The mechanism of trafficking-deficient HERG proteins, especially the role of endoplasmic rieticulum stress(ERS),has not been systematic and comprehensive study till now. Our previous research showed that HERG-A561V mutant can activates ATF6 which was the activating transcription factor of ERS, and thapsigargin can rescue the defective trafficking and function of mutant HERG proteins. It indicated that endoplasmic rieticulum stress impaired HERG mutants trafficking. In this study, we will continue to demonstrate the effects of ERS and ERS related drugs on HERG A561V and HERG E637K mutations trafficking defect using gene transfection,molecular biology and patch clamp techniques. We will also use perfusion system for mouse heart perfusion to explore the effects of ERS on HERG trafficking in HERG-A561Vmutant mouse models. The project will indentify the specific mechanism of HERG trafficking defect and and provide theoretical basis for the prevention and therapeutic target unique for LQTS.