ROLE OF POTASSIUM CHANNELS IN FRIBRILLATORY CONDUCTION

钾通道在颤动传导中的作用

• 批准号: 7314389
• 负责人: Jose S Jalife
• 金额: $ 32.76万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7314389
• 关键词: arrhythmia; atrial fibrillation; calcium flux; calcium ion; cardiac myocytes; cell cell interaction; gene expression; gene mutation; genetic regulation; genetically modified animals; heart; heart conduction system; heart dimension /size; heart electrical activity; heart function; ion transport; laboratory mouse; laboratory rat; molecular biology; molecular pathology; myocardium; potassium channel; protein quantitation /detection; sodium ion; tissue /cell preparation; transfection; ventricular fibrillation; voltage /patch clamp

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.

该项目旨在提高对钾渠道在控制中的作用的理解 频率依赖性心脏激发，间歇性波传播和原纤维传导。我们 提出一种多学科的方法，以调查正常和合作角色 强大的内向整流器Kir2.1（KCNJ2）频道发挥的异常兴奋性 对于IK1和延迟的整流器HERG（KCNH2）和KVLQT1（KCNQ1;/Mink（KCNE1），形成 分别携带IKR和IK的频道。我们的主要重点是程度的方式 LK1的内向矫正和Ikrand IK的门控动力学单独或组合，修改能力 当与解剖学或功能障碍相互作用时，心脏电波会传播 他们的道路。我们的总体假设是，IK1，LKR和/或LK的密度变化具有清晰的 对兴奋性和传导的后果，因此对空间分布的动力学， 纤颤期间通过心房和心室肌肉传播的间歇小波。我们的 方法跨越了三个不同级别的整合：细胞，二维心肌细胞单层 还有三维心脏。在细胞级别（特定目标1），我们利用了 分子生物学，病毒转移和斑块夹紧以明确测试这样的想法 存在不变的兴奋性钠和/或钙电流，抗震后的耐磨性 依赖速率的激发受IK1整流度和IKR和/或IKS门控动力学的控制。在二维级别（特定目标2），我们研究并量化了 这三种不同电流在波浪形成和现象中的个人作用 “漩涡脱落”。最后，在整个心脏的水平上（特定目标3），我们使用转基因 方法和光学映射以研究遗传的电生理后果 KIR通道中的突变导致外部IK1密度更大；以及将iks引入 小鼠基因组在转子和VF的动力学上及其通过自主输入的修饰。 成功实现我们的目标应有助于阐明波浪破裂的分子机制 在心脏纤维化中。提出的工作与对促进性的理解直接相关 特定钾通道的功能收益变化的影响已显示出在 某些临床状况，包括持续的AF，短QT综合征和特发性VF。