2020-08-012024-05-15https://scholars.lib.ntu.edu.tw/handle/123456789/663092Sudden cardiac death (SCD) due to malignant ventricular arrhythmia is a devastating clinical manifestation. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is defined as SCD due to abnormal calcium release and polymorphic ventricular tachycardia in the absence of structural heart disease and other identifiable causes. Importantly, there is no clinical predictor for CPVT and it is very difficult to identify or even treat these patients before SCD occurs. Therefore, identification of genetic predictor(s) is critical. Previous studies have identified genetic mutations in ryanodine receptor 2 gene (RYR2) and calsequestrin 2 gene (CASQ2) responsible for CPVT. However, the genetic basis for CPVT in Taiwan is largely unknown. All the possible CPVT patients in Taiwan were mis-classified as idiopathic ventricular fibrillation (IVF) because of lack of genetic study. We propose a 3-year project to identify possible variants or mutations for CPVT in Taiwan, and use a novel zebrafish model to elucidate the functionalities of these mutations. In the first year, we plan to identify CPVT patients from those IVF patients with RYR2 or CASQ2 mutation by performing high-throughput next-generation deep sequencing of the coding regions of RYR2 and CASQ2 genes. In the second year, we will establish a transgenic zebrafish model and induced pluripotent stem cell (iPSC) model of CPVT. We will study the electrophysiological phenotypes, using dual voltage and calcium optical mapping system to assess susceptibility to abnormal calcium release and ventricular arrhythmia. Finally in the third year, we will use chemical screening to find novel agents which may attenuate or prevent arrhythmogenic electrophysiological phenotypes in the zebrafish and iPSC models of CPVT. These agents may become a promising treatment for CPVT in the future, which implicates our study a so-called translational research.catecholaminergic polymorphic ventricular tachycardia； sudden cardiac death； mutation； induced pluripotent stem cell； zebrafish