Stretch-Dependent Calcium Signaling in Heart

心脏中拉伸依赖性钙信号传导

• 批准号: 8586548
• 负责人: William Jonathan Lederer
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586548
• 关键词: Affect; Behavior; Birth; Calcium; Calcium Signaling; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Coupled; Cytoskeleton; Dependence; Diastole; Disease; Duchenne muscular dystrophy; Dystrophin; Foundations; Functional disorder; Goals; Heart; Heart Diseases; High Prevalence; Image; Investigation; Lead; Length; Mediating; Methods; Microtubules; Modeling; Mus; Muscle Cells; Muscular Dystrophies; Patients; Physiological; Process; Property; Research; RyR2; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Scientist; Signal Transduction; Stress; Stretching; Systole; Technology; Time; Ventricular; Wild Type Mouse; Work; abstracting; experience; flash photolysis; heart cell; heart function; heart rhythm; in vivo; innovation; male; mdx mouse; mouse model; new technology; novel; patch clamp; research study; response; tool

Abstract Ca2+ sparks in heart have been shown by the PI to occur under physiological conditions during diastole and systole. They not only underlie the normal [Ca2+]i transient but have been found to be critically important in mediating the cellular response to stress and disease, contributing to contractile and arrhythmic dysfunction in conditions ranging from calcium overload to the cardiomyopathy of muscular dystrophy. Recently, work by the PI shows that physiologic stretch, such as that experienced by a myocyte during diastolic filling, dramatically alters Ca2+ spark occurrence transiently in normal cardiac ventricular myocytes. This behavior depends on microtubules affecting the release mechanisms of the sarcoplasmic reticulum (SR). Despite the importance of this new discovery one year ago, we have only now developed the additional tools needed to investigate how dynamic length changes can affect the triggering of Ca2+ sparks under diverse conditions. Using these new tools, we observe (in preliminary investigations) that stretch-dependent changes in Ca2+ sparks are even larger than previously observed and appear to arise from a transient increase in the the sensitivity of ryanodine receptors (RyR2s). Additional preliminary work shows that, surprisingly, this transient increase in Ca2+ sparks underlies the activation of arrhythmogenic Ca2+ waves at a very low rate in heart cells from control mice, but at a much higher rate in myocytes from mdx mice, the murine model of Duchenne muscular dystrophy, or from control mice with excessive calcium in the SR. The tools developed by the PI and his colleagues will enable an innovative state-of-the-art investigation into how cardiac Ca2+ signaling is modulated by physiological stretch. The proposed work seeks to investigate stretch-dependent Ca2+ sparks and Ca2+ waves in 1. control ventricular myocytes; 2. ventricular myocytes in which RyR2 properties have been altered; 3. ventricular myocytes when microtubules are modulated; 4. ventricular myocytes from dystrophin null (mdx) mice. The planned research should reveal for the first time the importance of stretch in normal and pathological Ca2+ signaling of cardiac ventricular myocytes. The work will therefore provide not only fundamental new information on normal cellular behavior but also on mechanisms of arrhythmogenesis. Furthermore it will lay the foundation for novel therapies for diverse heart diseases including Duchenne muscular dystrophy.

抽象的 PI已显示出心脏中的Ca2+火花在舒张期间发生在生理条件下 和收缩。它们不仅是正常[Ca2+] i的瞬态的基础，而且在 介导细胞对压力和疾病的反应，导致收缩和心律不齐的功能障碍 从钙超负荷到肌肉营养不良的心肌病的疾病。最近，工作 PI表明生理拉伸，例如舒张期肌细胞经历的延伸，急剧 在正常心室心肌细胞中瞬时变化Ca2+火花出现。这个行为取决于 影响肌质网（SR）释放机理的微管。尽管很重要 这一新发现一年前，我们现在才开发了所需的其他工具来研究如何 动态长度变化会影响在不同条件下Ca2+火花的触发。使用这些新 工具，我们观察到（在初步调查中）CA2+火花的伸展依赖性变化更大 比以前观察到的，似乎是由于ryanodine的灵敏度的瞬时提高而产生的 受体（RYR2S）。其他初步工作表明，令人惊讶的是，Ca2+火花的这种短暂增加 在对照小鼠的心脏细胞中，心律失常Ca2+波的激活是基础 MDX小鼠的肌细胞，Duchenne肌肉营养不良的鼠模型或来自 控制小鼠在SR中钙过多。 PI及其同事开发的工具将启用 对心脏Ca2+信号如何通过生理调节的创新的最新研究 拉紧。提议的工作旨在研究1。 心室心肌细胞； 2。ryR2特性改变的心室心肌细胞； 3。心室 微管调节时的心肌细胞； 4。肌营养不良蛋白NULL（MDX）小鼠的心室心肌细胞。这 计划的研究应首次揭示正常和病理CA2+的伸展运动的重要性 心室心肌细胞的信号传导。因此，这项工作不仅将提供基本的新 有关正常细胞行为的信息，也了解心律失常发生的机制。此外，它将放置 包括Duchenne肌肉营养不良在内的多种心脏病的新型疗法基础。