Development of Atrial Impulse Initiation and Conduction

心房冲动起始和传导的发展

• 批准号: 7067152
• 负责人: GREGORY E MORLEY
• 金额: $ 41.26万
• 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/7067152
• 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（由申请人提供）：心房节律紊乱是最常见的持续性心律失常类型，并显著导致心脏相关发病率和死亡率。许多心脏节律紊乱的电生理学基础在心脏发育的早期就已形成。虽然许多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意义的理解仍然存在重大差距。特别是，我们知道很少的电生理特性的主要心房结构在发展过程中，以及他们的改变如何有助于一个致心律失常的基板。这个建议的重点是发展方面的冲动启动和起源心房传导。我们将检验的中心假设是，窦房结中的冲动起始和通过心房到房室结的协调传导是由离子通道和连接蛋白表达的发育调节引起的。我们将通过追求以下3个具体目标来测试这个假设：具体目标1。确定伴随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。具体目标2.确定小鼠窦房结和心房中连接蛋白表达的发育变化在冲动起始和传播中的作用。具体目标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贡献。我们的总体目标是产生的信息，将直接影响我们的基本电生理事件的哺乳动物心脏发育及其在房性心律失常的形成中的作用的理解。我们的研究结果预计将对人类健康产生重大影响，因为它们将使我们能够形成新的策略来预防严重频繁发生的心律失常。