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：
8302308
负责人：
LEIGHTON T. IZU
金额：
$ 38.12万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8302308
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+依赖性心律失常是心源性猝死的主要原因，经常在心肌中意外出现。拟议的工作旨在检验关键细胞内 Ca2+ 信号蛋白的空间重塑可能是这种功能障碍的基础的假设。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的变化（~10%），也可以显着改变 Ca2+ 控制系统的稳定性。当蛋白质簇靠得更近时，就会出现剧烈的不稳定性，并将正常的细胞稳定性转变为致心律失常的底物。拟议的工作将把心脏 Ca2+ 信号传导的数学模型与单细胞、小梁和整个心脏的关键实验研究结合起来，以确定异常 Ca2+ 信号如何在细胞水平上产生并影响心脏的电活动。 Ryanodine 受体 (RyR) 在交界肌浆网中形成簇，并构成心脏的 Ca2+ 释放单位 (CRU)。 CRU 与附近含有 L 型 Ca2+ 通道 (LTCC) 的肌膜或横管膜并列。去极化时，LTCC 触发 CRU 产生 Ca2+ 火花，同步时产生 [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 CRU，因为局部 [Ca2+]i 不足以激活 CRU 中的 RyR。然而，在特定疾病状态下重塑 CRU 的空间分布可能会改变安全系数并导致 CRU 的异常触发。如果这种情况频繁发生，原本正常的 Ca2+ 火花将在细胞水平上引发导致心律失常的高 Ca2+ 传播波。这种升高的 Ca2+ 波的传播波可以激活内向电流，从而产生期外收缩和心律失常。使用两种容易出现意外 Ca2+ 依赖性心律失常发生的动物模型，PI 将研究 CRU 空间重塑是心律失常功能障碍的基础或导致心律失常功能障碍的核心假设。将检查表达遗传定义的常见肥厚性心肌病（FHC）的小鼠和自发性高血压大鼠。将解决三个问题：（1）根据新的、最先进的数学模型，肌节缩短是否会破坏 Ca2+ 控制系统的稳定性？ (2) 如果是这样，缩短 CRU 间距的药理学方法是否也会产生 Ca2+ 不稳定？ (3) 最后，具有无法解释的 Ca2+ 依赖性心律失常发生的动物模型是否揭示了其心律失常对 CRU 间隔的相同依赖性？总之，计划中的工作将提供心脏 Ca2+ 信号传导和心律失常发生的新信息，并为治疗令人困惑和迄今为止无法解释的 Ca2+ 依赖性心律失常的新方法奠定基础。公共卫生相关性：钙依赖性心律失常是心源性猝死的主要原因。意想不到的是在心肌中。拟议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。这些研究将数学模型、超级计算机模拟、最先进的成像和心脏病模型结合在一起，以研究这些关键分子空间分布的细微变化如何引发心律失常和心源性猝死。这些研究将为治疗令人困惑且迄今为止无法解释的钙依赖性心律失常的新方法奠定基础。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Measuring the metrics: Correlating t-tubule structure and muscle contraction in the intact heart.

测量指标：关联完整心脏中的 T 管结构和肌肉收缩。

DOI：
10.1016/j.yjmcc.2015.05.015
发表时间：
2015
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Chen-Izu,Ye;Izu,LeightonT
通讯作者：
Izu,LeightonT

Sequential dissection of multiple ionic currents in single cardiac myocytes under action potential-clamp.

DOI：
10.1016/j.yjmcc.2010.12.020
发表时间：
2011-03
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Banyasz T;Horvath B;Jian Z;Izu LT;Chen-Izu Y
通讯作者：
Chen-Izu Y

An emerging antiarrhythmic target: late sodium current.

DOI：
10.2174/1381612820666141029111729
发表时间：
2014-12
期刊：
Current pharmaceutical design
影响因子：
3.1
作者：
T. Bányász;N. Szentandrássy;J. Magyar;Zoltán Szabó;P. Nanasi;Y. Chen-Izu;L. Izu
通讯作者：
T. Bányász;N. Szentandrássy;J. Magyar;Zoltán Szabó;P. Nanasi;Y. Chen-Izu;L. Izu

Beta-adrenergic stimulation reverses the I Kr-I Ks dominant pattern during cardiac action potential.

DOI：
10.1007/s00424-014-1465-7
发表时间：
2014-11
期刊：
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
影响因子：
4.5
作者：
Banyasz, Tamas;Jian, Zhong;Horvath, Balazs;Khabbaz, Shaden;Izu, Leighton T.;Chen-Izu, Ye
通讯作者：
Chen-Izu, Ye

Une cellule type?