Calcium Signaling, Metabolism, and EC Coupling in Heart

心脏中的钙信号传导、代谢和 EC 耦合

• 批准号: 7664177
• 负责人: Joshua I Goldhaber
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664177
• 关键词: 3-Dimensional; Accounting; Affect; Aftercare; Architecture; Calcium; Calcium Signaling; Calcium Spikes; Cardiac; Cells; Cleaved cell; Coupling; Dependence; Dihydropyridine Receptors; Disruption; Energy Metabolism; Failure; Heart; Heart failure; Infarction; Investigation; Ischemia; Knockout Mice; L-Type Calcium Channels; Lead; Measurement; Measures; Metabolic; Metabolic stress; Metabolism; Methods; Modeling; Mus; Muscle Cells; Myocardial Ischemia; Myocardium; Numbers; Oryctolagus cuniculus; Pathology; Physiological reperfusion; Probability; Procedures; Process; Reperfusion Injury; Reperfusion Therapy; Resistance; Ryanodine; Signal Transduction; Sodium; Sodium-Calcium Exchanger; Staging; Structure; System; Testing; Tubular formation; Ventricular; Wild Type Mouse; abstracting; design; functional loss; inhibitor/antagonist; insight; loss of function; novel; prevent; research study

Project Summary/Abstract The applicant¿s long-term aims are to continue studies on calcium signaling, excitation-contraction (EC) coupling, and the dependence of these processes on energy metabolism in cardiac muscle. The specific aims are to study ventricular cells from rabbits and mice (including cardiac-specific sodium-calcium exchanger knock-out mice) to: 1) investigate calcium signaling and EC coupling in remodeled cells from the peri-infarct zone in rabbits. This will include an assessment of whether loss of L-type calcium channel function can account for failure of EC coupling and whether significant alterations in transverse-tubules, ryanodine and dihydropyridine receptors are involved in the failure of these cells; 2) investigate the effect of metabolic inhibition on the function and structure of couplons in rabbit ventricular myocytes. This will include a measurement of the minimum number of L-type calcium channels in a couplon and the way that metabolic inhibition affects their function. In particular, alterations in calcium spark and spike formation and cellular microarchitecture of the transverse-tubule system as a cause of the functional loss of couplons during metabolic inhibition will be considered; 3) study the resistance of sodium-calcium exchanger knock-out mice to metabolic stress. This will include an investigation of the hypothesis that metabolic inhibition prevents activation of reverse sodium-calcium exchange in wild-type mice, resulting in disruption of the calcium-induced calcium release mechanism of EC coupling. In contrast, it is hypothesized that sodium-calcium exchanger knock-out mice do not require sodium-calcium exchange for EC coupling and are therefore resistant to the effects of metabolic inhibition. The consequences of inhibiting sodium-calcium exchange activation on calcium spike latency will be examined. These experiments are, among other things, designed to explain the importance of diadic cleft calcium in the trigger process. Methods include measuring calcium spike probabilities and their latency distributions in rabbits and mice before and after treatment with metabolic inhibitors. In addition the methods include recently developed procedures for reconstructing the 3-dimensional architecture of the transverse¿tubule system and the 3-dimensional distribution of ryanodine and dihydropyridine receptors in peri-infarct cells and cells treated with metabolic inhibitors.

项目摘要/摘要 申请人的长期目的是继续研究钙信号传导，兴奋 - 收缩（EC） 耦合以及这些过程对心肌能量代谢的依赖性。具体目标 正在研究兔子和小鼠的心室细胞（包括心脏特异性钠 - 钙库交换器 淘汰小鼠）至：1）研究来自侵袭周期的重塑细胞中的钙信号传导和EC耦合 兔子的区域。这将包括评估L型钙通道功能是否可以 解释EC耦合失败以及横向管，ryanodine和 二氢吡啶受体参与这些细胞的衰竭。 2）研究代谢的影响 抑制兔室心肌细胞中夫妻的功能和结构。这将包括一个 一对夫妇的L型钙通道的最小数量和代谢的方式 抑制会影响其功能。特别是，钙火花和尖峰形成以及细胞微体系结构的改变 横管系统的原因是代谢期间夫妻的功能丧失 将考虑抑制作用； 3）研究钠 - 钙交换器敲除小鼠对代谢的抗性 压力。这将包括对代谢抑制阻止激活的假设的投资 野生型小鼠的反钠钙交换，导致钙诱导的钙破坏 EC耦合的释放机制。相比之下，假设钠钙交换器敲除 小鼠不需要钠钙交换进行EC耦合，因此对 代谢抑制。抑制钙升钙峰值激活钙的后果 将检查延迟。这些实验是旨在解释的重要性 触发过程中的di​​acic裂钙钙。方法包括测量钙尖峰的可能性及其 用代谢抑制剂治疗前后，兔子和小鼠的潜伏期分布。另外 方法包括最近开发的程序，用于重建3维体系结构 横向小管系统以及ryanodine和二氢吡啶受体的3维分布 用代谢抑制剂处理的细胞和细胞。