Stretch-Dependent Calcium Signaling in Heart

心脏中拉伸依赖性钙信号传导

• 批准号: 8029454
• 负责人: William Jonathan Lederer
• 金额: $ 37.5万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8029454
• 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; 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

DESCRIPTION (provided by applicant): 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 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. PUBLIC HEALTH RELEVANCE: Contraction and the heart rhythm are regulated by calcium inside of heart cells. This calcium level is now known to be set in part by changes in the cell length (these changes are also called "stretch"), a surprising result that was discovered recently by the scientists working on this proposal. The planned work will examine such stretch-dependent changes in cellular calcium and function and determine how stretch underlies normal and defective heart function.

描述（由申请人提供）：PI已显示出心脏中的Ca2+火花在舒张期和收缩期的生理条件下发生。它们不仅是正常的[Ca2+] I瞬态的基础，而且在介导细胞对压力和疾病的反应中至关重要，这在钙过载到肌肉性营养不良的心肌病等范围内导致收缩和心律不齐的功能障碍。最近，PI的工作表明，舒张期在舒张期填充过程中经历的生理拉伸，例如在正常心室心肌细胞中瞬时地出现Ca2+火花。这种行为取决于影响肌质网（SR）释放机制的微管。尽管这一新发现是一年前的重要性，但我们现在才开发出了研究动态长度变化如何影响CA2+火花在不同条件下的触发所需的其他工具。使用这些新工具，我们观察到（在初步研究中）Ca2+火花的拉伸依赖性变化甚至比以前观察到的大，并且似乎是由于ryanodine受体（RYR2S）的敏感性的短暂提高而产生的。 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. PI及其同事开发的工具将对心脏CA2+信号如何通过生理延伸来调节心脏CA2+信号传导的最新研究。拟议的工作旨在研究1。对照心室心肌细胞的伸展依赖的Ca2+火花和Ca2+波。 2。ryR2特性改变的心室心肌细胞； 3。调节微管时心室心肌细胞； 4。肌营养不良蛋白NULL（MDX）小鼠的心室心肌细胞。计划的研究应首次揭示在心脏心肌细胞的正常和病理Ca2+信号传导中拉伸的重要性。因此，这项工作不仅将提供有关正常细胞行为的基本新信息，还将提供心律失常发生的机制。此外，它将为包括Duchenne肌肉营养不良在内的多种心脏病的新疗法奠定基础。 公共卫生相关性：收缩和心律受心脏细胞内部钙调节。现在已知该钙水平部分由细胞长度的变化设置（这些变化也称为“拉伸”），这是一个令人惊讶的结果，这是该提案的科学家最近发现的。计划的工作将检查细胞钙和功能的这种拉伸依赖性变化，并确定拉伸如何构成正常和有缺陷的心脏功能。