CALCIUM SIGNALING IN HEART FAILURE

摘要人类心力衰竭是一种病因多样的临床综合征。 以心脏收缩减弱为特征的。尽管有很多人 原因，初步实验表明心力衰竭(HF)可能有 在细胞和分子水平上是一种常见的病理。少年派有 发现钙离子内流触发[Ca]i的能力降低 2+]i在心衰动物心肌细胞上的瞬变。 这种缺陷称为细胞性心衰，伴发时会导致临床心衰。 通过β-AR脱敏和/或下调。我们在中国的观察 压力过载HF得到了初步研究结果的有力支持 基因靶向扩张型心肌病心衰小鼠模型(MLP基因敲除 和病毒性心肌病心衰(CVB3小鼠)。这引发了 在HF的动物模型中，至少有两个特征的可能性 随着时间的推移而发展：细胞性HF和β-AR脱敏和/或 下调监管。我们提议的工作将在 使用最先进的方法，包括高速 共聚焦[Ca~(2+)]i成像和全细胞膜片钳技术我们 将通过测量膜来检查兴奋-收缩(EC)耦合 记录全细胞[Ca~(2+)]i瞬变时的电流、Ca~(2+)火花和 细胞收缩。 在拟议的工作期间将讨论三个具体问题。 (1)。哪些EC耦合缺陷是细胞性HF的基础和/或因素？ (2)。BetaAR信号如何影响HF中的EC偶联缺陷？ (3)。特定的药物和分子疗法如何改变 高频的EC耦合缺陷？这个项目采用了开发的新方法。 用高时间和空间分辨率的(Ca~(2+)]I成像的PI 调查心力衰竭。拟议的工作应该增加具体的知识 对HF的细胞和分子缺陷的研究，并为 治疗心力衰竭的新方法。

Human heart failure is a clinical syndrome of diverse etiology characterized by weakened cardiac contractions. Despite the many causes, preliminary experiments suggest that heart failure (HF) may have a common pathology at the cellular and molecular levels. The PI has identified a reduction in the ability of Ca2+ influx to trigger the [Ca 2+]i transient in ventricular myocytes from the hearts of animals in HF. This defect, called cellular HF , leads to clinical HF when accompanied by betaAR desensitization and/or downregulation. Our observation in pressure overload HF is strongly supported by preliminary findings with gene targeted mouse models of dilated cardiomyopathy HF (MLP knockout mouse) and viral myocardiopathy HF(CVB3 mouse). This raises the possibility that in animal models of HF, there are at least two features that develop over time: cellular HF and betaAR desensitization and/or down-regulation. Our proposed work will examine this hypothesis at the cellular level using state-of-the-art methods including high-speed confocal [Ca 2+]i imaging and whole cell patch-clamp techniques. We will examine excitation-contraction (EC) coupling by measuring membrane currents while recording whole-cell [Ca 2+]i transients, Ca2+ sparks and cellular contractions. Three specific questions will be addressed during the proposed work. (1). What EC coupling defects underlie and/or contribute to cellular HF? (2). How does betaAR signaling affect the EC coupling defects in HF? (3). How do specific pharmacological and molecular therapies alter the EC coupling defects in HF? This project exploits new methods developed by the PI using (Ca 2+]i imaging at high temporal and spatial resolution to investigate HF. The proposed work should increase specific knowledge of the cellular and molecular defects in HF and lay the foundation for novel therapeutic approaches to the treatment of HF.