Calcium signaling and cardiac arrhythmias

钙信号传导和心律失常

• 批准号: 6631296
• 负责人: William Jonathan Lederer
• 金额: $ 34.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6631296
• 关键词: action potentials; arrhythmia; beta adrenergic receptor; calcium channel; calcium flux; calcium indicator; cardiac myocytes; guinea pigs; heart electrical activity; laboratory mouse; laboratory rat; neuromuscular transmission; sarcoplasmic reticulum; single cell analysis; sudden cardiac death; tissue /cell culture; voltage /patch clamp

Cardiac arrhythmias are a leading cause of death in humans and occur in diverse conditions. The proposed research seeks to identify and characterize fundamental mechanisms that underlie fatal cardiac arrhythmias. Specific cellular and molecular events that trigger arrhythmias will be examined to test the hypothesis that changes in subcellular calcium signaling contribute to arrhythmogenesis. Animal models of altered electrical activity in the heart will be studied at the single cells level using whole patch clamp methods and confocal calcium imaging. Isolated cardiac myocytes from control and transgenic animals and cells expressing specific constructs will be used in the planned work. Preliminary results have demonstrated calcium-dependent links between altered electrical behavior and the expression of specific cellular proteins that are being examined in Project 1 (Russo), Project 2 (Marks) and Project 3 (Kass). The proteins of particular interest include beta1AR, beta2AR, RyR2, FKB12, FKBP12.6, SCN5A and mutations of these proteins. The proposed work examines how expression of the target proteins affects intracellular [Ca2+]i and also Ca2+-dependent membrane currents. This examination will explore the importance of the action potential shape and duration on [Ca2+]i signaling in the proposed experimental models. Additionally the relationship between SR Ca2+ content and Ca2+ release (as measured by Ca2+ sparks and the global (Ca2+) transient) will be examined with these molecular models. The experiments carried out in this project should thus provide fundamental new information on the arrhythmogenic roles played by the betaAR signaling system, sarcolemmal ion channels and the intracellular Ca2+ release channels.

心律不齐是人类死亡的主要原因，并且发生在各种条件下。拟议的研究旨在识别和表征致命心律不齐的基本机制。将检查触发心律不齐的特定细胞和分子事件，以检验以下假设，即亚细胞信号传导的变化有助于心律失常。将使用整个贴片夹方法和共聚焦钙成像研究心脏中电活动改变的动物模型。来自对照和转基因动物和表达特定构建体的细胞的分离心肌细胞将用于计划的工作。初步结果表明，在项目1（RUSSO），项目2（标记）和项目3（KASS）中所检查的特定细胞蛋白的表达之间的钙依赖性联系与特定细胞蛋白的表达之间。特别感兴趣的蛋白质包括beta1ar，beta2ar，ryr2，fkb12，fkbp12.6，scn5a和这些蛋白质的突变。提出的工作研究了靶蛋白的表达如何影响细胞内[Ca2+] I以及Ca2+依赖性膜电流。该检查将探讨在提出的实验模型中[Ca2+] I信号传导的动作电位形状和持续时间的重要性。另外，将使用这些分子模型检查SR Ca2+含量与Ca2+释放（通过Ca2+ Spark和全局（Ca2+）瞬态）之间的关系。因此，该项目中进行的实验应提供有关Betaar信号系统，肌膜离子通道和细胞内CA2+释放通道的心律失常作用的基本新信息。