Molecular Mechanisms of Cardiac Arrhythmias

描述（由申请人提供）：仅在美国，心律失常每年就导致30多万人猝死。我们实验室正在研究心律失常的发病机制。我们关注两种心律失常：长qt综合征（LQT）和特发性心室颤动（IVF），这两种疾病都会导致年轻健康个体的猝死。在这个项目过去的8年里，我们专注于LQT和IVF的遗传学和体外电生理。与其他科学家一起，我们已经确定了LQT和IVF发病的遗传途径。由于缺乏患者的新鲜心脏组织，在组织和器官水平上进一步探索LQT和IVF的致病机制是不可能的。在我们提出的研究中，我们计划建立和表征LQT-和ivf -动物模型，其中SCN5A（心脏钠通道基因）突变被设计到小鼠基因组中，以进一步探索心律失常的病因。我们已经成功建立了针对SCN5A突变（N1325S）的LQT和室性心律失常小鼠模型。我们的心律失常小鼠的特征导致了早期和后去极化（EADs和DADs）是室性心动过速（VT）和心室颤动（VF）的基础的工作假设。在拟开展的研究中，我们计划继续研究LQT小鼠模型，以揭示心律失常的详细分子机制，并建立体外受精和获得性LQT小鼠模型并对其进行表征。我们的具体目标是：

DESCRIPTION (provided by applicant): Cardiac arrhythmias account for more than 300,000 sudden deaths each year in the U.S. alone. Our laboratory is investigating the pathogenesis of cardiac arrhythmias. We focus on two arrhythmic disorders: long-QT syndrome (LQT) and idiopathic ventricular fibrillation (IVF), both of which cause sudden death in the young, otherwise healthy, individuals. During the past 8 years of this project, we focused on genetics and in vitro electrophysiology of LQT and IVF. Together with other scientists, we have defined a genetic pathway for pathogenesis of both LQT and IVF. Further exploration of pathogenic mechanisms of LQT and IVF at the tissue and organ level is impossible because of lack of fresh heart tissues from patients. In the proposed studies we plan to develop and characterize LQT- and IVF-animal models in which SCN5A (the cardiac sodium channel gene) mutations are engineered into the mouse genome to further explore the etiology of arrhythmogenesis. We have successfully established a mouse model for LQT and ventricular arrhythmias by targeting an SCN5A mutation (N1325S). Characterization of our arrhythmic mice has led to the working hypothesis that early and after depolarizations (EADs and DADs) are the substrate for ventricular tachycardia (VT) and ventricular fibrillation (VF). In the proposed studies we plan to continue to study the mouse model for LQT to uncover detailed molecular mechanisms of cardiac arrhythmias, and to generate and characterize mouse models for IVF and acquired LQT. Our specific aims are: (1) To investigate whether over-expression of an LQT-causing mutation of SCN5A in the mouse heart will trigger electrophysiological remodeling; (2) To systematically dissect EADs and DADs induced by a genetic LQT mutation; (3) To systematically determine the effects of representative agents from each class of antiarrhythmic drugs on VT/VF and correlate the findings with results on EADs/DADs; (4) To characterize SCN5A mutations associated with IVF and acquired LQT using the transgenic mouse technology. The successful accomplishment of goals in this proposal will provide a fundamental understanding of the pathogenic mechanisms of cardiac arrhythmias. Evaluation of animal models will help define the physiological and cellular processes involved in arrhythmogenesis, and bridge the gap between the in vitro biophysical defects and the in vivo whole animal phenotype characterized by arrhythmia susceptibility. These studies may provide a new framework for the rational design of therapeutic agents.