药物抑制Ikr/hERG、L-Ca2+等通道导致QT间期延长，伴有Tdp恶性心律失常，易致猝死，此现象限制了多种药物的临床应用并成为新药研发的障碍，但目前缺乏有效的防治手段及药物。基于此本项目以药物作用及安全性评价的重要靶点hERG及L型-钙通道为靶标，从多层面探讨影响hERG蛋白稳定表达的细胞内调控机制，揭示药物影响hERG蛋白逆行转运的内吞、降解及再循环的信号通路及内在联系,明确影响通道蛋白成熟、定位及功能表达关键靶蛋白，发掘可靶向逆转hERG蛋白转运障碍的物质，将氧化应激-内质网应激过程与降解途径有机联系在一起，从全新角度阐述药物诱发LQTS的机制；LncRNA作为一种全新调控分子，探讨其对hERG、Ca2+通道的调控作用，为临床防治提供新靶点；在此基础上应用hiPSC-CM细胞模型筛选评价中药的逆转作用，并与西药分析比较，探寻其中的特点和规律，实现中药靶向性治疗acLQTS的目标。

Inhibition of Ikr/hERG or L-Ca2+ channel by drugs will prolong QT interval, cause malignant arrhythmia accompanied with torsade de pointes (TdP) and even sudden death. The phenomenon limited the clinical application of a variety of agents and impeded new drug research and development. Regrettably, effective prevention/cure drugs or other methods are still in short. Based on these, we planned to study the intracellular regulatory mechanisms affecting the stable expression of hERG protein by targeting hERG and L-Ca2+ channel which are crucial for acting mechanism and safety evaluation of drugs, and reveal the signaling pathways of hERG protein retrograde trafficking including endocytosis, degradation and recycling and their internal relations. We aimed to explicit key target proteins responsible for hERG maturation, location and functional expression, and then search for effective drugs to reverse the adverse effect based on the targets. Meanwhile, we organically combine oxidative stress, endoplasmic reticulum stress with degradation of hERG protein, which will expound the mechanism of drug-induced LQTS from a new perspective. Furthermore, we will explore the regulation function of lncRNAs, a new class of regulatory molecules, on hERG and calcium channels, thus provide new targets for clinical prevention and treatment. Finnally, we will apply cell models of hiPSC-CM to screen and assess the effective drugs to rescue adverse effects, and make comparision with western medicine to clarify the characters and patterns for drug-hERG interaction, to achieve the goal of targeting therapy for treating acLQTS through traditional Chinese medicine.