Purkinje Cells and Arrhythmia Mechanisms

浦肯野细胞和心律失常机制

基本信息

批准号：
8129941
负责人：
Glenn I Fishman
金额：
$ 67.41万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8129941
关键词：
Acute Animal Model Anti-Arrhythmia Agents Arrhythmia Biological Assay Canis familiaris Cardiac 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)Engineering Functional disorder Galactosidase Gene Expression Genetic 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 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. 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.

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死亡的主要原因。这些死亡的一半突然发生，通常来自急性缺血，心脏病或遗传综合症（包括通道病和心肌病）的心室心律失常。专门的心脏传导系统（CCS）组成了一个异质的细胞网络，该网络在整个心肌中精心策划了电激发浪潮的启动和传播。 Purkinje细胞构成了CCS中最远端的成分和实质性的，但是间接的实验数据积累了支持Purkinje细胞扮演关键机械作用的概念，触发了广泛的威胁生命的心律失常。但是，我们对浦肯野细胞生物学的理解中的主要差距已经阻止了这种认识被转化为新型的抗心律失常策略。通过我们最近对传导系统中表达的新细胞粘附分子的Contactin-2鉴定，我们建立了新的工具来识别，分离和表征鼠Purkinje细胞。使用这些工具，我们提出了一系列研究，以研究呼普京网络发展的依赖性调节，通过正常和患病心脏中的Contactin-2对心脏电生理的调节，以及调节Purkinje细胞中病理重塑的依赖性机制。公共卫生相关性：叙事叙事心脏病是美国和其他发达国家死亡的主要原因，这些死亡中几乎一半突然发生在心律异常中。我们的研究旨在理解负责这些致命性心律失常的机制，并确定潜在的新治疗靶标。