Control of Local Calcium Signaling in the Heart

心脏局部钙信号传导的控制

• 批准号: 7617524
• 负责人: ERIC A SOBIE
• 金额: $ 32.14万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617524
• 关键词: Address; Affect; Buffers; Calcium; Calcium Signaling; Cardiac; Cells; Characteristics; Chemicals; Computer Analysis; Computer Simulation; Coupling; Data; Dependence; Diffusion; Disease; Ectopic beats; Engineering; Environment; Event; Feedback; Foundations; Functional disorder; Goals; Heart; Heart failure; Investigation; Ions; Lead; Learning; Measurable; Measures; Mechanics; Microscope; Molecular; Muscle Cells; Oryctolagus cuniculus; Physiology; Play; Process; Production; Property; Rattus; Recovery; Regulation; Reliance; Resolution; Role; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Shapes; Signal Transduction; Techniques; Testing; Time; Translating; Ventricular; Work; computer studies; heart cell; heart function; insight; research study; voltage

DESCRIPTION (provided by applicant): Each heartbeat requires the coordination of electrical excitation and mechanical contraction in every heart cell, a process that requires a relatively small amount of calcium (Ca) entering the cell to trigger a much larger release of Ca from the sarcoplasmic reticulum (SR). In healthy hearts, this process of Ca-induced Ca release (CICR) is surprisingly stable despite the fact that it relies on positive feedback. However, mis-regulation of CICR has recently been shown to play a central role in disease states such as heart failure. Although a considerable amount has been learned about how the elementary units of Ca release, Ca sparks, are triggered, very little is known about how these events terminate or whether defective termination plays a role in disease. The goal of this proposal is to investigate fundamental molecular mechanisms by which Ca sparks terminate and how the termination of these events affects the regulation of CICR. The aims of this proposal will be to perform critical experimental tests that address several fundamental unanswered questions regarding how Ca sparks are triggered and how they terminate. To accomplish the Specific Aims of this proposal, experiments will be performed on single ventricular myocytes isolated from rat and rabbit hearts. Sub-cellular changes in Ca concentration in these cells will be tracked with a fluorescent indicator and a confocal microscope. Computer modeling, based on the Pi's previous work, will be used to interpret data and develop hypotheses. This work will provide fundamental new information about how Ca is regulated in normal hearts. This can provide a foundation for better understanding how Ca can be mis-regulated in disease. This work therefore fits in with the Pi's long term objective of understanding electrical and chemical signaling in healthy and diseased hearts.

描述（由申请人提供）：每个心跳都需要每个心脏细胞中电激发和机械收缩的协调，这一过程需要相对较少量的钙（CA）进入细胞，以触发从核质网（SR）中释放出更大的Ca的释放。在健康的心脏中，尽管CA诱导的CA释放（CICR）的过程依赖于积极的反馈，但这种CA诱导的CA释放（CICR）还是令人惊讶的稳定。然而，最近已显示对CICR的错误调节在心力衰竭等疾病状态中起着核心作用。尽管已经了解了相当多的了解CA释放的基本单位，CA火花是如何触发的，但对于这些事件如何终止或有缺陷的终止是否在疾病中起作用，知之甚少。该提案的目的是研究CA终止的基本分子机制，以及这些事件的终止如何影响CICR的调节。该提案的目的是进行重要的实验测试，以解决有关CA火花如何触发以及它们终止的几个基本未解决的问题。 为了实现该提案的具体目的，将对从大鼠和兔心脏分离的单个心室心肌细胞进行实验。这些细胞中Ca浓度的亚细胞变化将使用荧光指示器和共聚焦显微镜跟踪。根据PI先前的工作，计算机建模将用于解释数据和发展假设。 这项工作将提供有关在正常心脏中如何调节CA的基本新信息。这可以为更好地理解疾病中如何误导CA的基础。因此，这项工作符合PI的长期目标，即了解健康和患病心脏中的电信号传导。