Molecular Mechanisms of Cardiac Arrhythmias

描述（由申请人提供）：仅在美国，心律失常每年就造成30多万例猝死。我们实验室正在研究心律失常的发病机制。我们专注于两种心脏病：长QT综合征（LQT）和特发性室颤（IVF），这两种疾病都会导致年轻人的猝死，否则健康的个体。在过去的8年里，我们专注于LQT和IVF的遗传学和体外电生理学。与其他科学家一起，我们已经确定了LQT和IVF发病机制的遗传途径。由于缺乏新鲜的患者心脏组织，在组织器官水平上进一步探讨LQT和IVF的致病机制是不可能的。在拟议的研究中，我们计划开发和表征LQT和IVF动物模型，其中SCN 5A（心脏钠通道基因）突变被工程化到小鼠基因组中，以进一步探索胚胎发生的病因。我们已经成功地建立了LQT和室性心律失常的小鼠模型，通过靶向SCN 5A突变（N1325 S）。对我们的实验小鼠的表征导致了工作假设，即早期和后去极化（埃兹和DAD）是室性心动过速（VT）和心室颤动（VF）的底物。在拟议的研究中，我们计划继续研究LQT的小鼠模型，以揭示心律失常的详细分子机制，并生成和表征IVF和获得性LQT的小鼠模型。我们的具体目标是： (1)目的：（1）研究引起LQT突变的SCN 5A基因在小鼠心脏中的过表达是否会引起电生理重构;（2）系统分析LQT基因突变引起的埃兹和DAD;（3）系统测定各类抗心律失常药物的代表性药物对VT/VF的作用，并将其结果与埃兹/DAD的结果相关联;（4）利用转基因小鼠技术研究与IVF和获得性LQT相关的SCN 5A突变。 本提案中目标的成功实现将为心律失常的致病机制提供基本的理解。动物模型的评价将有助于确定参与心律失常发生的生理和细胞过程，并弥合体外生物物理缺陷与以心律失常易感性为特征的体内整体动物表型之间的差距。这些研究可能为合理设计治疗药物提供新的框架。

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.