ROLE OF POTASSIUM CHANNELS IN FRIBRILLATORY CONDUCTION

钾通道在颤动传导中的作用

• 批准号: 7496152
• 负责人: Jose S Jalife
• 金额: $ 37.17万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-13 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496152
• 关键词: Achievement; Arrhythmia; Biochemical; Calcium; Cardiac; Cavia; Cell Communication; Cells; Cellular biology; Collaborations; Communication; Computer software; Condition; Daily; Electronics; Failure; Frequencies; Gap Junctions; Gene Mutation; Gene Transfer; Genotype; Heart; Heart Atrium; Heterogeneity; Individual; Infarction; Investigation; Ion Channel; Isoproterenol; Kinetics; Kir2.1 channel; Lead; Link; Maps; Mediating; Mink; Modification; Molecular; Molecular Biology; Mus; Muscle; Muscle Cells; Mutagenesis; Mutation; Myocardial Ischemia; Optics; Patients; Play; Potassium; Potassium Channel; Production; Protein Overexpression; Proteins; Protocols documentation; Rate; Rattus; Recovery; Regulation; Research Personnel; Resources; Role; Services; Sheep; Sodium; Structure; Sympathetic Nervous System; Syndrome; Tachyarrhythmias; Testing; Time; Transgenes; Transgenic Mice; Transgenic Organisms; Ventricular; Viral; Virus; Work; density; gain of function; gain of function mutation; genetic manipulation; human study; insight; monolayer; mouse genome; mutant; patch clamp; programs; response; simulation; tool; two-dimensional

This project is aimed at increasing the understanding of the role of potassium channels in the control of frequency dependent cardiac excitation, intermittent wave propagation and fibril latory conduction. We propose a multi-disciplinary approach to investigate the individual and cooperative roles in normal and abnormal excitability played by the strong inward rectifier Kir2.1 (KCNJ2) channel that is responsible for IK1 and the delayed rectifiers HERG (KCNH2) and KvLQT1(KCNQ1;/minK(KCNE1) forming the channels that carry IKr and IKs, respectively. Our main focus is the manner in which the degree of inward rectification of lK1 and the gating kinetics of IKrand IKs alone or in combination, modify the ability of cardiac electrical waves to propagate when interacting with anatomical or functional obstacles in their path. Our general hypothesis is that changes in the density of IK1, lKr and/or lK have sharp consequences on excitability and conduction, and thus on the dynamics of spatially distributed, intermittent wavelets that propagate through atrial and ventricular muscle during fibrillation. Our approaches span three different levels of integration: the cell, the two-dimensional myocyte monolayer and the three-dimensional heart. At the cellular level (Specific Aim 1), we take advantage of the tools of molecular biology, viral transfer and patch clamping to test unambiguously the idea that, in the presence of unchanged excitatory sodium and/or calcium currents, post-repolarization refractoriness and rate-dependent excitation are controlled by both the degree IK1 rectification and the kinetics of IKr and/or IKs gating. At the two-dimensional level (Specific Aim 2), we investigate and quantify the individual roles of these three different currents in wavebreak formation and the phenomenon of "vortex shedding". Finally, at the level of the whole heart (Specific Aim 3), we use a transgenic approach and optical mapping to investigate the electrophysiological consequences of genetic mutations in Kir channels leading to greater outward IK1 density; and the effects of introducing IKs into the mouse genome on the dynamics of rotors and VF and their modification by autonomic input. Successful achievement of our objectives should help clarify the molecular mechanisms of wavebreak in cardiac fibrillation. The work proposed is directly relevant to the understanding of the pro-arrhythmic effects of gain-of-function changes in specific potassium channels that have been shown to occur in certain clinically conditions, including persistent AF, the short QT syndrome and idiopathic VF.

该项目旨在加深对钾通道在控制中作用的了解。 频率相关的心脏兴奋、间歇波传播和纤维传导。我们 提出一种多学科方法来研究正常和合作中的个人和合作角色 负责的强内向整流器 Kir2.1 (KCNJ2) 通道发挥异常兴奋性 对于 IK1 和延迟整流器 HERG (KCNH2) 和 KvLQT1(KCNQ1;/minK(KCNE1) 形成 分别承载 IKr 和 IK 的通道。我们主要关注的是程度的方式 lK1的内向整流和IKrand IKs的门控动力学单独或组合，改变能力 当与解剖或功能障碍相互作用时心脏电波的传播 他们的道路。我们的一般假设是 IK1、lKr 和/或 lK 的密度变化具有急剧的变化 对兴奋性和传导的影响，从而对空间分布的动态产生影响， 颤动期间通过心房和心室肌肉传播的间歇小波。我们的 方法跨越三个不同的整合水平：细胞、二维肌细胞单层 以及立体的心。在细胞水平（具体目标 1），我们利用以下工具 分子生物学、病毒转移和膜片钳技术明确地测试了这样的想法： 存在未改变的兴奋性钠和/或钙电流、复极后不应性 和速率依赖性激发由 IK1 整流程度和 IKr 和/或 IKs 门控动力学控制。在二维层面（具体目标 2），我们调查并量化 这三种不同的电流在波浪形成中的各自作用以及 “涡流脱​​落”。最后，在整个心脏水平（具体目标 3），我们使用转基因 方法和光学映射来研究遗传的电生理后果 Kir 通道突变导致外向 IK1 密度更大；以及引入 IK 的效果 小鼠基因组对转子和 VF 动力学的影响及其通过自主输入的修改。 成功实现我们的目标应有助于阐明波浪破碎的分子机制 在心脏颤动中。所提出的工作与对促心律失常的理解直接相关 特定钾通道功能获得性变化的影响已被证明发生在 某些临床病症，包括持续性房颤、短 QT 综合征和特发性心室颤动。