儿茶酚胺敏感性多形性室速 (CPVT) 是一种具有遗传特征的原发性心电疾病，以运动或情绪激动后出现晕厥、猝死为主要临床表现。研究证实心肌细胞中钙离子释放通道 (RyR2) 遗传变异是CPVT的主要原因，先证者中约有50%存在RyR2的突变。我们前期的工作围绕与RyR2的遗传突变开展，集中于研究突变位点的定位以及突变对蛋白结构、构象变化和功能的影响，并深入探讨致病的机制。近期，我们从一例CPVT患者身上筛查到一个全新的RyR2突变位点A690E，预实验结果表明该位点位于RyR2三维结构中与调控蛋白FKBP结合部位。基于预实验的结果，我们提出该突变通过干扰RyR2-FKBP正常结合，进而造成RyR2功能紊乱的科学假说。我们将构建转基因小鼠，采用生化、电生理、结构生物学及细胞生物学等方法，在动物、组织、细胞和分子层面探讨该突变对RyR2结构和功能的影响。为阐明CPVT的分子机制奠定基础。

Catecholaminergic polymorphous ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia, characterized as exercise- or emotion-induced arrhythmias, syncope, and sudden death. It has been demonstrated that mutations in gene encoding calcium release channels (ryanodine receptor type 2, RyR2) in cardiac myocyte directly linked to CPVT, almost 50% of proband have mutant RyR2. Our previous studies mainly focus on the arrhythmogenic mechanism of genetic mutations in defects in the structure, conformation dynamics, and functions in RyR2. Very recently, we have identified a new RyR2 mutation in a CPVT patient, A690E. Our preliminary structural analysis indicated the mutation is located in the binding site of FKBP, a RyR2 modular protein. Our hypothesis is that mutation affects the normal interaction between RyR2 and FKBP, causes RyR2 channel instability. We will test this hypothesis by generating a knock-in mouse, and investigate the relationship between RyR2 mutation and CPVT at molecular, cellular, tissue, and animal model levels. This knowledge will significantly advance our understanding of the structural basis of the mutant RyR2 dysfunction in CPVT.