Calcium Entrained Arrhythmias

钙引起的心律失常

• 批准号: 8403962
• 负责人: MOHSIN Saleet JAFRI
• 金额: $ 93.43万
• 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: 2011-04-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403962
• 关键词: Achievement; Action Potentials; Address; Affect; Arrhythmia; Behavior; Binding Proteins; Biological; Biological Models; Calcium; Calcium Oscillations; Calcium Signaling; Calsequestrin; Cardiac; Cardiac Death; Catecholamines; Cavia; Cell model; Cells; Cellular biology; Cessation of life; Complex; Computational algorithm; Computer Simulation; Data; Defect; Disease; Distant; Ectopic beats; Environment; Event; Experimental Models; Foundations; Functional disorder; Funding; Genetic; Genetic Models; Health; Heart; Heart Diseases; Heart failure; Hereditary Disease; Hour; Human; Inherited; Investigation; Laboratories; Lead; Legal patent; Literature; Mammals; Membrane Potentials; Methods; Modeling; Molecular; Mus; Muscle Cells; Mutation; Myocardial Infarction; Myocardium; Organelles; Outcome; Paper; Physiology; Point Mutation; Preparation; Process; Proteins; Publishing; Research Project Grants; Resolution; Role; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Series; Shapes; Signal Transduction; Signaling Protein; Structure; Structure of purkinje fibers; Systems Biology; Testing; Time; TimeLine; Tissue Engineering; Tissues; Travel; Ventricular; Ventricular Tachycardia; Work; computer cluster; data modeling; genetic regulatory protein; heart cell; heart rhythm; improved; mathematical model; molecular scale; mouse model; novel; novel therapeutic intervention; public health relevance; research study; success; sudden cardiac death; three dimensional structure

DESCRIPTION (provided by applicant): Calcium (Ca2+) dependent arrhythmias have been identified as a significant health problem leading to ventricular tachycardia, fibrillation and death. The exact mechanism by which these arrhythmias arise remains a critically important yet vexing problem. We hypothesize that these Ca2+ dependent arrhythmias occur through a process in which a propagating wave of elevated calcium travels through heart cells and thereby activates and entrains electrical activity. The proposals PIs (Lederer, Jafri, and Winslow) will combine state-of- the art computational modeling with novel laboratory experiments in a multi-scale approach to determine how the calcium signaling defect develops and critically test the hypothesis. This systems biology investigation will examine the molecular physiology of cardiac Ca2+ signaling at high temporal and spatial resolution under normal and pathological conditions. It will utilize the unusually powerful approach of specifically examining the molecular pathophysiology of the Ca2+ dependent arrhythmia using the molecular disease, catecholaminergic polymorphic ventricular tachycardia (CPVT) caused by an extremely well-defined process - point mutations of critical Ca2+ regulatory proteins. We will examine how mutations in the calcium release channel (ryanodine receptor type 2, RyR2) and the Ca2+ binding protein, calsequestrin (CASQ2) contribute to Ca2+ dependent arrhythmogenesis. Mouse models of these two arrhythmias will be used to enable advanced cell biology investigations. The work will be made more general by also including an examination of Ca2+ overload arrhythmias in mouse and guinea pig. The planned investigation will encompass multiple scales: from the molecular defect, to cellular Ca2+ dysfunction to tissue arrhythmia using both mathematical modeling and biological experiments. The project will address the following four specific aims: 1) How do Ca2+sparks trigger and sustain calcium waves? 2) How do Ca2+waves propagate from cell to cell? How do Ca2+waves entrain electrical activity? 3) How do specific mutations in RyR2 and CASQ2 affect Ca2+sparks, Ca2+waves and the propagation of Ca2+waves from cell to cell? 4) How does the 3D organization of the heart affect Ca2+ entrained arrhythmogenesis? This work should provide fundamental new understanding of the heart and the role of Ca2+ in electrical dysfunction and arrhythmia and lay the foundation for new therapeutic approaches.

描述（由申请方提供）：钙（Ca 2+）依赖性心律失常已被确定为导致室性心动过速、纤颤和死亡的重大健康问题。这些心律失常发生的确切机制仍然是一个非常重要但令人烦恼的问题。我们假设这些Ca 2+依赖性心律失常是通过一个过程发生的，在这个过程中，一个升高的钙离子传播波穿过心脏细胞，从而激活并引起电活动。PI（Lederer、Jafri和温斯洛）的提案将联合收割机最先进的计算建模与多尺度方法中的新型实验室实验相结合，以确定钙信号缺陷如何发展，并严格检验假设。这项系统生物学研究将在正常和病理条件下以高时间和空间分辨率研究心脏Ca 2+信号传导的分子生理学。它将利用异常强大的方法，特别是检查分子病理生理学的钙依赖性心律失常，使用分子疾病，儿茶酚胺能多态性室性心动过速（CPVT）引起的一个非常明确的过程-点突变的关键Ca 2+调节蛋白。我们将研究钙释放通道（ryanodine受体2型，RyR 2）和钙结合蛋白，钙螯合蛋白（CASQ 2）的突变如何促进钙依赖性神经元生成。这两种心律失常的小鼠模型将用于进行先进的细胞生物学研究。这项工作将更加普遍，还包括在小鼠和豚鼠中检查钙超载心律失常。计划的研究将包括多个尺度：从分子缺陷，细胞Ca 2+功能障碍，组织心律失常，使用数学建模和生物实验。 该项目将解决以下四个具体目标：1）Ca 2+火花如何触发和维持钙波？2)Ca 2+波如何从细胞传播到细胞？Ca 2+波如何引起电活动？3)RyR 2和CASQ 2中的特定突变如何影响Ca 2+火花，Ca 2+波以及Ca 2+波从细胞到细胞的传播？4)心脏的3D组织如何影响Ca 2+夹带的心肌发生？ 这项工作应该提供对心脏的基本新理解以及Ca 2+在电功能障碍和心律失常中的作用，并为新的治疗方法奠定基础。