Reorganization of calcium signaling in heart failure

心力衰竭中钙信号的重组

• 批准号: 7052035
• 负责人: Sandor Gyorke
• 金额: $ 3.94万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-20 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052035
• 关键词: action potentials; apical membrane; biological signal transduction; calcium channel; calcium flux; cardiac myocytes; cytoplasm; heart failure; heart function; laboratory rat; pharmacokinetics; phosphorylation; sarcoplasmic reticulum; voltage /patch clamp

DESCRIPTION (provided by applicant): This research will be done primarily in Slovak Republic as an extension of NIH grant #HL074045. The overall goal of this proposal is to elucidate the changes of calcium signaling mechanisms in dyads of mammalian cardiac muscle cells during heart failure. These structures contain clusters of L-type calcium channels (DHPRs) in opposition to clusters of ryanodine receptor calcium release channels functionally coupled by calcium ions. Alterations in calcium signaling during excitation-contraction coupling contribute to the decreased performance of failing hearts. The changes in calcium signaling steps during activation of calcium release by DHPRs and their relationship to the ultrastructural organization of dyads and the topology of channels in the excitation-contraction coupling units will be determined. To this end, measurements of the kinetics of whole-cell calcium currents, whole-cell calcium transients, and dyadic calcium release events (calcium spikes) will be carried out. These measurements will be supplemented by morphological analysis of the volume and surface densities of the tubular system and of cisternal and longitudinal sarcoplasmic reticulum, and of colocalization between calcium channels and calcium release channels, using electron microscopy and confocal microscopy. Quantitative analysis of the kinetics of calcium current and calcium release in parallel will be used to estimate parameters of calcium signaling critical for control of gradation and efficiency of excitation-contraction coupling. Computer simulation of experiments will be used to ascertain possible mechanisms and to design experiments with high predictive power. Understanding the abnormalities of cardiac E-C coupling in heart failure is important since it might become a strategic site for therapeutic intervention. Furthermore, defining the relationships between the spatial organization of channel clusters and their calcium signaling has a broader significance for understanding processes such as synaptic transmission, neuroendocrine secretion and regulation of vascular tone.

描述（由申请人提供）：这项研究将主要在斯洛伐克共和国进行，作为NIH赠款＃HL074045的扩展。该提案的总体目标是阐明心力衰竭期间哺乳动物心肌细胞二元的钙信号传导机制的变化。这些结构包含L型钙通道（DHPR）的簇，与钙离子功能偶联的瑞氨烷受体钙释放通道的簇。激发收缩偶联过程中钙信号传导的改变会导致心脏失败的性能下降。 DHPRS激活钙释放过程中的钙信号传导步骤的变化及其与二元组织的超微结构组织的关系以及激发量耦合单元中通道的拓扑拓扑的变化。为此，将进行全细胞钙电流，全细胞钙瞬变和二元钙释放事件（钙尖峰）的测量。这些测量值将通过对管状系统的体积和表面密度以及脑膜和纵向肌质网的体积和表面密度进行补充，并使用电子显微镜和共焦显微镜使用钙通道和钙释放通道之间的共定位。对钙电流和钙释放的动力学的定量分析将用于估计钙信号的参数，对于控制渐变和激发反应偶联的效率至关重要。实验的计算机模拟将用于确定可能的机制，并用高预测能力设计实验。了解心力衰竭中心脏E-C耦合的异常非常重要，因为它可能成为治疗干预的战略部位。此外，定义通道簇的空间组织与其钙信号传导之间的关系对于理解过程（例如突触传播，神经内分泌分泌和血管张力调节调节）具有更广泛的意义。