Development of Atrial Impulse Initiation and Conduction

心房冲动起始和传导的发展

• 批准号: 6920853
• 负责人: GREGORY E MORLEY
• 金额: $ 42.25万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-20 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6920853
• 关键词: arrhythmia; atrium; cardiogenesis; electrophysiology; embryo /fetus; gap junctions; heart conduction system; heart electrical activity; heart pacemaker tissue; intercellular connection; laboratory mouse; membrane channels; membrane potentials; myocardium; neuromuscular transmission; potassium channel

DESCRIPTION (provided by applicant): Atrial rhythm disorders are the most common type of sustained arrhythmias and contribute significantly to cardiac related morbidity and mortality. The electrophysiological substrates for many cardiac rhythm disturbances are set in place early in heart development. Although a number of genes and signaling pathways involved in specification and differentiation of the early embryonic heart, major gaps in our understanding of the functional implications of such findings remain. In particular, we know little about the electrophysiologic properties of the major atrial structures during development and how their alteration contributes to an arrhythmogenic substrate. This proposal focuses on the developmental aspects of impulse initiation and the genesis of atrial conduction. The central hypothesis we will test is that impulse initiation in the sinus node and coordinated conduction through the atria to the AV node results from the developmental modulation of ion channels and connexin expression. We will test this hypothesis by pursuing the following 3 specific aims: SPECIFIC AIM 1. Determine the electrophysiological features that accompany the formation of a mature sinoatrial node with emphasis on the role played by the inward rectifier current (IK1). SPECIFIC AIM 2. Determine the role of developmental changes of connexin expression in impulse initiation and propagation in the mouse sinus node and atria. SPECIFIC AIM 3. Determine the relative contributions of cellular excitability and intercellular coupling in impulse initiation and atrial conduction. Our overall goal is to generate information that will directly impact our understanding of the basic electrophysiological events underlying mammalian heart development and their role in the formation of atrial arrhythmias. Our findings are expected to have a major impact on human health, because they will allow us to form new strategies to prevent major frequently occurring cardiac arrhythmias.

描述(申请人提供)：房性心律失常是最常见的持续性心律失常类型，对心脏相关的发病率和死亡率有很大影响。许多心律紊乱的电生理基础在心脏发育的早期就已经存在。尽管一些基因和信号通路参与了早期胚胎心脏的特化和分化，但我们对这些发现的功能含义的理解仍然存在重大差距。特别是，我们对发育过程中主要心房结构的电生理特性以及它们的改变如何导致心律失常的底物知之甚少。这项建议侧重于脉冲启动的发育方面和心房传导的起源。我们将检验的中心假设是，窦房结的冲动起始和通过心房到房室结的协调传导是离子通道和连接蛋白表达的发育调节的结果。我们将通过追求以下三个具体目标来验证这一假说：具体目的1.确定伴随着成熟窦房结形成的电生理特征，重点是内向整流电流(Ik1)所起的作用。目的2.研究小鼠窦房结和心房肌中间隙连接蛋白表达的发育性变化在冲动起始和传播中的作用。特异性目的3.确定细胞兴奋性和细胞间耦合在冲动启动和心房传导中的相对作用。我们的总体目标是产生信息，这些信息将直接影响我们对哺乳动物心脏发育的基本电生理事件及其在房性心律失常形成中的作用的理解。我们的发现有望对人类健康产生重大影响，因为它们将使我们能够形成预防主要频繁发生的心律失常的新策略。