Sarcomere Length Shortening and the Destabilization of the Ca2+ Control System in

肌节长度缩短和 Ca2 控制系统的不稳定

• 批准号: 7591444
• 负责人: LEIGHTON T. IZU
• 金额: $ 36.13万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591444
• 关键词: Abbreviations; Address; Affect; Animal Model; Arrhythmia; Arts; Behavior; Calcium; Calcium Signaling; Calcium ion; Cardiac; Cardiac Myocytes; Cells; Computer Simulation; Congestive Heart Failure; Contractile Proteins; Contractile System; Coupling; Dependence; Development; Disease; Disease model; Ectopic beats; Equation; Equilibrium; Event; Familial Hypertrophic Cardiomyopathy; Foundations; Frequencies; Functional disorder; Generations; Goals; Grant; Heart; Heart Diseases; Human; Hypertrophic Cardiomyopathy; Hypertrophy; Image; Inbred SHR Rats; Incidence; Investigation; Lead; Length; Link; Membrane; Methods; Microfilaments; Modeling; Mus; Muscle Cells; Mutation; Myocardium; Patients; Phosphorylation; Preparation; Probability; Property; Proteins; Rattus; Relaxation; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Safety; Sarcomeres; Sarcoplasmic Reticulum; Signal Transduction; Signaling Protein; Spatial Distribution; System; Testing; Transgenic Mice; Troponin T; Tubular formation; Ventricular; Work; computer code; mathematical model; models and simulation; mouse model; novel strategies; public health relevance; simulation; sudden cardiac death; supercomputer

DESCRIPTION (provided by applicant): Ca2+ dependent arrhythmias, a leading cause of sudden cardiac death, often arises unexpectedly in heart muscle. The proposed work seeks to examine the hypothesis that spatial remodeling of key intracellular Ca2+ signaling proteins may underlie this dysfunction. The has recently discovered in preliminary work that even a small (~10%) change in the spatial distribution of these proteins can dramatically alter the stability of the Ca2+ control system; as clusters of the proteins get closer together, dramatic instability arises and changes normal cellular stability into an arrhythmogenic substrate. The proposed work will combine mathematical modeling of cardiac Ca2+ signaling with critical experimental investigations in single cells, trabeculae, and whole heart to determine how abnormal Ca2+ signals arise at the cellular level and affect electrical activity in the heart. Ryanodine receptors (RyRs) form clusters in the junctional sarcoplasmic reticulum and constitute the Ca2+ release unit (CRU) of the heart. The CRUs are apposed to nearby sarcolemmal or transverse tubular membranes containing L-type Ca2+ channels (LTCC). On depolarization, the LTCC trigger the CRU to produce Ca2+ sparks which, when synchronized, produce a [Ca2+]i transient. When they are not synchronized, rare spontaneous Ca2+ sparks do not normally trigger nearby CRUs because local [Ca2+]i is insufficiently elevated to activate the RyRs in the CRU. Remodeling of the spatial distribution of the CRUs in specific disease state, however, may change that safety factor and contribute to the aberrant triggering of CRUs. Should this occur with great frequency, an otherwise normal Ca2+ spark will trigger an arrhythmogenic propagating wave of elevated Ca2+ at the cellular level. This propagating wave of elevated Ca2+ wave can activate inward current to produce extrasystoles and arrhythmias. Using two animal models prone to unexpected Ca2+ dependent arrhythmogenesis, the PI will investigate the core hypothesis that CRU spatial remodeling underlies or contributes to arrhythmic dysfunction. Mice expressing genetically defined familiar hypertrophic cardiomyopathy (FHC) and spontaneous hypertensive rats will be examined. Three questions will be addressed: (1) Does sarcomere shortening destabilize Ca2+ control system according to new, state- of-the-art mathematical models? (2) If so, can pharmacological means of shortening CRU spacing also produce Ca2+ instability? (3) Finally, do the animal models that have unexplained Ca2+ dependent arrhythmogenesis reveal the same dependence of their arrhythmias on CRU spacing? Taken together, the planned work will provide new information of cardiac Ca2+ signaling and arrhythmogenesis and lay the foundation for new approaches to treating perplexing and heretofore unexplained Ca2+ dependent arrhythmia PUBLIC HEALTH RELEVANCE: Calcium dependent arrhythmias, a leading cause of sudden cardiac death, often arises unexpectedly in heart muscle. The proposed work seeks to test the hypothesis that spatial remodeling of key intracellular calcium signaling proteins during the development of some heart diseases may underlie this dysfunction. These studies bring together mathematical modeling, supercomputer simulations, state-of-the-art imaging, and heart disease models to examine how even subtle changes in the spatial distribution of these key molecules can trigger arrhythmias and sudden cardiac death. These studies will lay the foundation for new approaches to treating perplexing and heretofore unexplained calcium dependent cardiac arrhythmias.

描述(申请人提供)：钙依赖型心律失常是导致心脏性猝死的主要原因之一，常意外出现在心肌。这项拟议的工作试图检验一种假说，即关键的细胞内钙信号蛋白的空间重构可能是这种功能障碍的基础。最近在初步工作中发现，即使这些蛋白质的空间分布发生很小(~10%)的变化也能极大地改变钙离子控制系统的稳定性；随着蛋白质簇越来越近，就会出现显著的不稳定，并将正常细胞的稳定性改变为致心律失常的底物。这项拟议的工作将结合心脏钙信号的数学建模和在单个细胞、小梁和整个心脏中进行的关键实验研究，以确定异常钙信号如何在细胞水平上产生并影响心脏的电活动。兰尼定受体(RyRs)在连接肌浆网中形成簇，构成心脏的钙释放单位(CRU)。CRU与邻近的含有L钙通道的肌膜或横管膜相对。在去极化时，LTCC触发CRU产生钙火花，当同步时，产生[钙]i瞬变。当它们不同步时，罕见的自发钙火花通常不会触发附近的CRU，因为局部[Ca~(2+)]i的升高不足以激活CRU中的RyR。然而，重塑CRU在特定疾病状态下的空间分布可能会改变该安全系数，并导致CRU的异常触发。如果这种情况发生的频率很高，原本正常的钙火花将在细胞水平上触发高钙致心律失常的传播波。这种高钙波的传播波可以激活内向电流，从而产生早搏和心律失常。使用两种易发生意外的钙依赖性心律失常的动物模型，PI将调查CRU空间重构是心律失常的基础或促成心律失常的核心假设。表达基因定义的常见肥厚型心肌病(FHC)的小鼠和自发性高血压大鼠将被检测。将讨论三个问题：(1)根据新的、最先进的数学模型，肌节缩短是否会破坏钙控制系统的稳定性？(2)如果是这样，缩短CRU间距的药物手段是否也会产生钙不稳定？(3)最后，尚未解释钙依赖心律失常发生的动物模型是否显示出它们的心律失常对CRU间距的同样依赖？综上所述，计划中的工作将提供心脏钙信号和心律失常发生的新信息，并为治疗令人困惑且迄今未解释的钙依赖型心律失常的公共卫生相关性奠定基础：钙依赖型心律失常是导致心脏性猝死的主要原因，通常发生在心肌中。这项拟议的工作试图测试这一假设，即在某些心脏病的发展过程中，关键的细胞内钙信号蛋白的空间重构可能是这种功能障碍的基础。这些研究将数学建模、超级计算机模拟、最先进的成像技术和心脏病模型结合在一起，研究这些关键分子的空间分布即使是细微的变化也会引发心律失常和心脏猝死。这些研究将为治疗令人困惑和迄今无法解释的钙依赖型心律失常的新方法奠定基础。