基于基因敲入小鼠的SCN3B突变导致房颤机理研究

Atrial fibrillation (AF) is the most common cardiac arrhythmia that substantially increases risk of stroke, heart failure and sudden death, and has become one of the most important health issues for the Chinese people. The mechanism of AF is not clear and needs to be further defined. Genetic determinants have played important roles in the structure and electrical remodeling of heart, leading to AF. In our previous study, we found that the A130V mutation of sodium channel beta subunit 3 (SCN3B) caused lone AF, and demonstrated that SCN3B is a novel AF pathogenic gene. However, the detailed mechanism needs be studied further. To identify the mechanism by which SCN3B mutation causes AF, we generated knockin mouse model with the SCN3B A130V mutation, and in this project, we will perform （1）ECG analysis for monitoring the arrhythmia; (2) Intracardiac electrophysiological examination to reveal the substrate of atrial fibrillation caused by SCN3B A130V mutation; (3) Isolation of the cardiomyoctes of A130V knockin mice and patch clamp tests to search the effect of A130V mutation on the sodium ion channel; (4) Through protein interaction research ，analyze the effect of A130V mutation on interaction of β3 and a subunit of sodium channel.The purpose of this project is to reveal the mechanism by which SCN3B mutation causes AF through studies using the mouse model, and the result may help recognize the insight of the pathology of AF, and to find novel strategy of treatment and prevention.

房颤为临床上最常见的心律失常，是引起心脑血管发病和死亡的重要病因，严重危害我国居民健康。房颤发生机制迄今仍未完全阐明，有待进一步研究。遗传基因是房颤致病的主要因素之一，申请人前期通过遗传学研究首次发现SCN3B A130V突变导致孤立性房颤，但其详细机制有待进一步明确。为深入研究SCN3B突变导致房颤的详细机制，申请人课题组构建了A130V突变基因敲入小鼠，现拟利用该小鼠模型，监测心电指标，分析其心律失常表型；进一步通过心内电生理实验，分析突变导致心律失常的生理学基础和电学机制，同时分离心肌细胞，利用细胞电生理实验研究突变对于细胞离子流和电生理特征的影响，最后通过蛋白质相互作用研究，分析A130V突变对β3亚基和a亚基蛋白质互作的影响。最终从器官－组织－细胞－分子层面深入探索SCN3B基因突变引起房颤的详细机制，以期进一步认识房颤发病机理，发现新的房颤治疗靶点和预防机制。

为深入研究SCN3B突变导致房颤的详细机制，申请人课题组构建了A130V突变基因敲入小鼠，利用该小鼠模型，监测心电指标，确认了其心律失常表型；进一步通过电生理实验，初步发现可其突变导致心律失常的生理学基础和电学机制，同时分离心肌细胞，利用细胞电生理实验研究突变对于细胞离子流和电生理特征的影响。项目对深入探索SCN3B基因突变引起房颤的详细机制，认识房颤发病机理，发现新的房颤治疗靶点和预防机制具有一定意义。