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

基本信息

批准号：
8103065
负责人：
LEIGHTON T. IZU
金额：
$ 38.38万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/8103065
关键词：
Abbreviations Address Affect Animal Model Arrhythmia 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 Health 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 simulation sudden cardiac death supercomputer

项目摘要

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（由申请人提供）：CA2+依赖性心律不齐，这是心脏猝死的主要原因，通常是心脏肌肉意外出现的。拟议的工作旨在检查以下假设：关键细胞内Ca2+信号蛋白的空间重塑可能是这种功能障碍的基础。最近在初步工作中发现的，即使这些蛋白质的空间分布发生较小（约10％）也可以显着改变Ca2+控制系统的稳定性。随着蛋白质的簇越来越近，出现剧烈的不稳定性并将正常的细胞稳定性变为心律失常基质。所提出的工作将结合心脏CA2+信号传导的数学模型与单个细胞，小梁和整个心脏的重要实验研究，以确定在细胞水平上如何出现异常的Ca2+信号并影响心脏中的电活动。 ryanodine受体（RYRS）在连接肌质网中形成簇，并构成心脏的Ca2+释放单元（CRU）。 CRUS置于附近的肌膜或横向管状膜中，其中包含L型Ca2+通道（LTCC）。在去极化时，LTCC触发CRU产生Ca2+火花，同步后会产生[Ca2+] i瞬态。当它们不同步时，罕见的自发CA2+火花通常不会触发附近的Crus，因为局部[Ca2+] i不足以升高以激活CRU中的Ryrs。但是，在特定疾病状态下，CRU的空间分布的重塑可能会改变安全因子，并导致CRU的异常触发。如果发生这种情况，则否则正常的Ca2+火花将触发升高Ca2+在细胞水平上的心律失常传播波。这种升高的Ca2+波的传播波可以激活向内的电流，以产生外交和心律不齐。使用两个容易出现CA2+依赖性心律失常发生的动物模型，PI将研究核心假设，即CRU空间重塑基础或导致心律失常功能障碍。将检查表达遗传定义熟悉的肥厚心肌病（FHC）和自发性高血压大鼠的小鼠。将解决三个问题：（1）肌节缩短是否会根据新的，现有的数学模型来破坏CA2+控制系统？（2）如果是这样，缩短CRU间距的药理学手段也可以产生CA2+不稳定吗？（3）最后，无法解释的Ca2+依赖性心律失常发生的动物模型表明其心律不齐对CRU间距的依赖性相同？综上所述，计划中的工作将提供心脏CA2+信号传导和心律失常的新信息，并为治疗困惑和迄今为止无法解释的CA2+依赖性心律失常的公共健康相关的新方法奠定了基础：钙依赖性心律失常，这是突然的心脏死亡的主要原因，这是突然的心脏，通常在心脏运动中出现意外。提出的工作旨在检验以下假设：在某些心脏病的发展过程中，关键细胞内钙信号蛋白的空间重塑可能是这种功能障碍的基础。这些研究汇集了数学建模，超级计算机模拟，最先进的成像和心脏病模型，以检查这些关键分子的空间分布的微妙变化如何触发心律失常和突然的心脏死亡。这些研究将为治疗困惑和迄今无法解释的钙依赖性心律失常的新方法奠定基础。