儿茶酚胺敏感性多形室速的胞内钙失稳机制

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited severe arrhythmia mainly occurring in young ages. Ventricular tachycardia usually occurs in mutant-harboring patients during sports or irritation, which may lead to sudden death. Mutations in the sarcoplasmic reticulum calcium release channel, known as ryanodine receptor-2 (RyR2), or calcium buffering protein, calseqiestrin-2 (CASQ2), have been identified to underlie CPVT. However, how the calcium signaling proteins leads to arrhythmic activity remains unclear, and how the mutations leads to abnormal molecular behaviors is being hotly debated. In the present proposal, using the mice model harboring the R2474S mutation in RyR2, unique techniques for in situ RyR2 characterization and optical tweezer technology, we will intensively study the effects of the R2474S mutation on the molecular properties of RyR2s, on the RyR2 interaction with its accessory protein FKBP12.6, and on the ?-adrenergic modulation of RyR2 behaviors. We will seek to explore the structure-function relationship of the mutant domain of RyR2 using structural biological methods. We will also visualize and analyze the abnormal intracellular calcium dynamics, especially the process for calcium sparks to trigger spiral waves. Based on the experimental results, model simulation will be used to integrate the molecular behavior of RyR2s and the global performance of arrhythmogenesis, providing fundamental cellular and molecular mechanisms of CPVT.

儿茶酚胺敏感性多形室速（CPVT）是主要见于青壮年中的遗传性严重心律失常，突变携带者常在运动或激动后突发室速，并可致猝死。该疾病与肌质网钙释放通道RyR2和钙缓冲蛋白CASQ2突变有关，但信号蛋白分子异常如何导致异常节律尚不清楚；突变的RyR2导致分子性质变化的机制尚在激烈争论。本项目以携带RyR2突变R2474S的小鼠为模型，运用本实验室有特色的RyR2原位研究技术、光镊技术深入分析RyR2突变对其分子自身性质的影响、对与其附件蛋白FKBP12.6结合的影响，对其接受β肾上腺素受体信号调控的影响，从结构生物学角度探索突变结构域结构与功能的关系，运用高速共聚焦成像技术研究突变分子产生钙信号的时空动态异常（特别是钙火花导致螺旋波的过程），通过数学建模，从实验到理论全面阐述CPVT的分子和细胞机制。

作为一种主要见于青壮年中的遗传性致死心律失常，儿茶酚胺敏感性多形室速（CPVT）与肌质网钙释放通道RyR2和钙缓冲蛋白CASQ2突变有关，但信号蛋白分子异常如何导致异常节律尚不清楚；突变的RyR2导致分子性质变化的机制尚在激烈争论。本项目以携带RyR2突变R2474S的小鼠为模型，运用本实验室有特色的RyR2原位研究技术、光镊技术深入分析了RyR2突变对其分子自身性质的影响、对与其附件蛋白FKBP12.6结合的影响，对其接受β肾上腺素受体信号调控的影响，从结构生物学角度探索突变结构域结构与功能的关系，运用高速共聚焦成像技术研究突变分子产生钙信号的时空动态异常（特别是钙火花导致螺旋波的过程），通过数学建模，从实验到理论全面阐述了CPVT的分子和细胞机制。