Purkinje Cells and Arrhythmia Mechanisms

描述（由申请人提供）： 心脏病仍然是美国和其他发达国家的主要死亡原因。这些死亡中有一半是突然发生的，通常是由于急性缺血、获得性心脏病或遗传性综合征（包括通道病和心肌病）引起的室性快速性心律失常。专门的心脏传导系统（CCS）包括细胞的异质网络，其协调整个心肌的电兴奋波的启动和传播。浦肯野细胞包括CCS的最远端组件，并且大量但间接的实验数据已经积累，支持浦肯野细胞在触发广泛的危及生命的室性心律失常中发挥关键机制作用的概念。然而，我们对浦肯野细胞生物学的理解存在重大差距，阻碍了这种认识转化为新的抗肿瘤策略。通过我们最近鉴定的接触蛋白-2，一种新的细胞粘附分子在传导系统中表达，我们已经建立了新的工具来识别，分离和表征小鼠浦肯野细胞。使用这些工具，我们提出了一系列的研究，以调查接触蛋白-2依赖的浦肯野网络的发展，心脏电生理的调节，在正常和患病的心脏，和接触蛋白-2依赖的机制，调节浦肯野细胞的病理性重塑。 公共卫生相关性： 项目叙述心脏病是美国和其他发达国家的主要死亡原因，其中近一半的死亡是由于心律异常而突然发生的。我们的研究旨在了解这些致命性心律失常的机制，并确定潜在的新治疗靶点。

DESCRIPTION (provided by applicant): PROJECT SUMMARY Heart disease remains the leading cause of death in the United States and other developed countries. Half of these deaths occur suddenly, typically from ventricular tachyarrhythmias that arise in the setting of acute ischemia, acquired heart disease or inherited syndromes including channelopathies and cardiomyopathies. The specialized cardiac conduction system (CCS) comprises a heterogeneous network of cells that orchestrate the initiation and propagation of a wave of electrical excitation throughout the myocardium. Purkinje cells comprise the most distal component of the CCS and substantial, but indirect experimental data has accumulated supporting the concept that Purkinje cells play a key mechanistic role triggering a broad range of life-threatening ventricular arrhythmias. However, major gaps in our understanding of Purkinje cell biology have prevented this realization from being translated into novel anti-arrhythmic strategies. Through our recent identification of contactin-2, a novel cell adhesion molecule expressed in the conduction system, we have established new tools to identify, isolate and characterize murine Purkinje cells. Using these tools, we propose a series of studies to investigate contactin-2 dependent regulation of Purkinje network development, the regulation of cardiac electrophysiology by contactin-2 in normal and diseased hearts, and contactin-2 dependent mechanisms regulating pathologic remodeling in Purkinje cells. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Heart disease is the leading cause of death in the United States and other developed countries and almost half of these deaths occur suddenly from heart rhythm abnormalities. Our research is directed toward understanding the mechanisms responsible for these lethal arrhythmias and identifying potential new therapeutic targets.