HUMAN ATRIAL FIBRILLATION--CHANGES IN CHANNEL EXPRESSION

人类心房颤动——通道表达的变化

• 批准号: 6030784
• 负责人: David R Van Wagoner
• 金额: $ 14.93万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6030784
• 关键词: action potentials; atrial fibrillation; calcium channel; cardiac myocytes; clinical research; gene expression; heart conduction system; heart electrical activity; human subject; human tissue; microelectrodes; potassium channel; voltage /patch clamp; voltage gated channel; western blottings

One million Americans suffer from atrial fibrillation, the most common chronic arrhythmia. Atrial fibrillation is responsible for significant discomfort, morbidity and mortality. The mechanisms involved in the perpetuation of atrial fibrillation are thought to include a shortening of the effective refractory period of the atrium, but the details of the electrophysiological remodeling which the atria undergoes are poorly understood. We propose to use a novel, highly integrated approach to explore the relationship between the electrophysiological properties of the intact, isolated atrial tissue, the distribution of K+ and Ca2+ currents in isolated myocytes, and the expression of specific K+ and ca2+ channel subunits in the membrane fractions of the same atrial tissue. The specific aims of the proposal are: 1)To evaluate the rate-dependent modulation of atrial wavelength (action potential duration, refractory period, and conduction velocity) in atrial tissue obtained from patients in normal sinus rhythm or in chronic atrial fibrillation. 2) To characterize the action potentials, the density of specific K+ components, and the density of voltage-gated Ca2+ current in myocytes isolated from the same atrial tissue used in - aim #1. 3)To determine the density and relative distribution of the K+ and CA2+ channel alpha subunits responsible for the functional currents measured in the same atrial tissue and myocytes used in aims #1 and #2. 4)To correlate the biochemical measurements (aim #3) with the electrophysiological measurements (aims #1 and #2), and with clinical measures of refractoriness obtained during surgical procedures. Microelectrode, bipolar and optical measurements of electrical activity in isolated human atrial tissue, perforated-patch whole cell recording of K+ and Ca2+ currents in individual atrial myocytes, and Western blot analysis of K+ and Ca2+ channel (x-subunits expression in atrial tissue and myocytes will be used to accomplish the experimental aims. The proposed experiments will provide novel and fundamental information on the impact of chronic atrial fibrillation on ion channel expression in the human atrium. This information is needed to identify novel, safer and more effective strategies for the treatment of this disabling arrhythmia, by identifying logical, specific molecular targets for future therapeutic interventions.

一百万美国人患有房颤，最多 常见的慢性心律失常。房颤负责 明显的不适，发病率和死亡率。机制 涉及房颤的永久性 包括缩短的有效耐火周期 中庭，但是电生理重塑的细节 心房经历的理解很少。我们建议使用 一种小说，高度综合的方法来探索这种关系 完整，分离的电生理特性之间 心房组织，孤立的K+和Ca2+电流的分布 心肌细胞以及特定K+和Ca2+通道的表达 同一心房组织的膜级分中亚基。这 该提案的具体目的是：1）评估依赖速率的 心房波长的调节（动作电位持续时间， 心房组织中的耐火周期和传导速度） 从正常窦性心或慢性心房中的患者获得 纤颤。 2）为表征动作电位，密度 特定的K+分量和电压门控Ca2+的密度 从与 - 目标＃1。 3）确定 K+和Ca2+通道α亚基负责功能 在相同的心房组织和肌细胞中测量的水流 目标＃1和＃2。 4）与生化测量相关联（目标 ＃3）进行电生理测量（目标＃1和＃2）， 并采用在 手术程序。微电极，双极和光学 孤立人心房中电活动的测量 组织，打孔的K+和Ca2+的全细胞记录 单个心肌细胞和蛋白质印迹分析中的电流 K+和Ca2+通道（X-亚基在心房组织中的表达和 心肌细胞将用于实现实验目的。 这 拟议的实验将提供新颖和基本的信息 关于慢性心房颤动对离子通道的影响 在人体中庭中的表达。需要此信息 确定小说，更安全，更有效的策略 通过识别逻辑，治疗这种残疾心律不齐的治疗 未来治疗干预措施的特定分子靶标。