Purkinje Cells and Arrhythmia Mechanisms

浦肯野细胞和心律失常机制

基本信息

批准号：
8644864
负责人：
Glenn I Fishman
金额：
$ 43.07万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644864
关键词：
Acute Animal Model Anti-Arrhythmia Agents Arrhythmia Biological Assay Canis familiaris Cardiac Cardiac Electrophysiologic Techniques Cardiac conduction system Cardiomyopathies Cause of Death Cell Adhesion Molecules Cell Cycle Cell Proliferation Cells Cellular biology Cessation of life Collaborations Communities Data Defect Developed Countries Development Developmental Biology Disease Distal Electrophysiology (science)Functional disorder Galactosidase Gene Expression Profile Genetic Genetic Engineering Heart Heart Diseases Inherited Ion Channel Ischemia Knockout Mice Knowledge Laboratories LacZ Genes Life Modeling Mouse Strains Mus Myocardium Nervous system structure Neurons Organism Pathologic Pattern Periodicity Play Predisposition Publishing Purkinje Cells Regulation Reporter Reporter Genes Research Research Personnel Resolution Role Sarcolemma Series Stress Structure of purkinje fibers Syndrome System Systems Biology Tachyarrhythmias Testing Transcript Transgenic Mice Translating United States Ventricular Ventricular Arrhythmia Work base contactin heart rhythm insight neural patterning new therapeutic target novel prevent public health relevance tool

项目摘要

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.

描述（由申请人提供）：项目摘要心脏病仍然是美国和其他发达国家的首要死因。其中一半的死亡是突然发生的，通常是由于急性缺血、获得性心脏病或遗传综合征（包括离子通道病和心肌病）引起的室性快速心律失常。专门的心脏传导系统（CCS）由异质细胞网络组成，负责协调整个心肌中电激发波的启动和传播。浦肯野细胞构成 CCS 的最远端成分，并且积累了大量但间接的实验数据，支持浦肯野细胞在触发广泛的危及生命的室性心律失常方面发挥关键机制作用的概念。然而，我们对浦肯野细胞生物学理解的重大差距阻碍了这种认识转化为新的抗心律失常策略。通过我们最近对 contactin-2（一种在传导系统中表达的新型细胞粘附分子）的鉴定，我们建立了新的工具来鉴定、分离和表征鼠浦肯野细胞。利用这些工具，我们提出了一系列研究来调查浦肯野网络发育的contactin-2依赖性调节、正常和患病心脏中contactin-2对心脏电生理学的调节，以及调节浦肯野细胞病理重塑的contactin-2依赖性机制。