ROLE OF POTASSIUM CHANNELS IN FRIBRILLATORY CONDUCTION

该项目旨在增加对钾通道在控制 频率依赖性心脏兴奋、间歇性波传播和纤维性传导。我们 提出了一个多学科的方法来调查个人和合作的作用，在正常和 由负责的强内向整流Kir2.1（KCNJ 2）通道发挥的异常兴奋性 对于IK 1和延迟整流器HERG（KCNH 2）和KvLQT 1（KCNQ 1;/minK（KCNE 1）， 分别携带IKr和IKs的通道。我们主要关注的是， IK 1的内向整流和IKrandIKs的门控动力学单独或组合， 当与解剖或功能障碍物相互作用时， 我们的一般假设是，IK 1，lKr和/或lK密度的变化具有明显的 对兴奋性和传导的影响，从而对空间分布的动力学， 在纤维性颤动期间通过心房和心室肌传播的间歇性小波。我们 方法跨越三个不同层次的整合：细胞，二维肌细胞单层， 和三维心脏。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来明确地测试这种想法， 存在不变的兴奋性钠和/或钙电流，复极后不应性 和速率依赖性兴奋的程度IK 1整流和IKr和/或IKs门控的动力学控制。在二维水平（具体目标2），我们调查和量化 这三种不同的电流在波浪破碎形成和现象的个别作用 “旋涡脱落”。最后，在整个心脏的水平上（具体目标3），我们使用转基因的 方法和光学作图来研究遗传性的电生理后果 Kir通道的突变导致更大的外向IK 1密度;以及将IKs引入 小鼠基因组的动态转子和VF和他们的修改自主输入。 我们的目标的成功实现将有助于阐明波裂的分子机制 心脏纤维性颤动所提出的工作直接关系到对亲生物学的理解。 已经证明发生在特定钾通道中的功能获得性变化的影响， 某些临床状况，包括持续性房颤、短QT综合征和特发性VF。

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.