Frank-Starling's Law of the Heart: Cellular Mechanisms

弗兰克-斯塔林心脏定律：细胞机制

• 批准号: 7901601
• 负责人: Pieter P. de TOMBE
• 金额: $ 37.03万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901601
• 关键词: Actins; Adopted; Affect; Binding; Cardiac; Cardiac Volume; Contractile Proteins; Data; Dependency; Filament; Fluorescent Probes; Funding; Goals; Grant; Head; Heart; Interruption; Ions; Kinetics; Length; Measurement; Mediating; Methods; Microfilaments; Modeling; Molecular; Mus; Muscle; Mutation; Myocardium; Myofibrils; Myosin ATPase; Myosin Light Chains; Operating System; Performance; Physiological; Physiological Processes; Post-Translational Protein Processing; Preparation; Process; Production; Property; Rattus; Regulation; Relaxation; Reporter; Research; Research Project Grants; Research Proposals; Role; Sarcomeres; Signal Transduction; Site; Starling (law); Stretching; Striated Muscles; Structure; Structure-Activity Relationship; System; Takeda brand of pioglitazone hydrochloride; Technical Expertise; Techniques; Testing; Thick; Thick Filament; Thin Filament; Threonine; Time; Transgenic Mice; Transgenic Organisms; Troponin; Troponin I; base; blebbistatin; genetic regulatory protein; inhibitor/antagonist; myosin-binding protein C; prevent; programs; protein complex; public health relevance; research study; response; skeletal; theories; two-dimensional

DESCRIPTION (provided by applicant): The Frank-Starling law of the heart describes the interrelationship between end-diastolic volume and cardiac ejection volume, a regulatory system that operates on a beat-to-beat basis. At the cellular level, sarcomere length (SL) dependent myofilament Ca2+ sensitivity underlies this phenomenon (length dependent activation-LDA). How the contractile apparatus transduces the information concerning SL is not known. The overall goal of our research is to elucidate the molecular mechanisms that underlie LDA. During the previous funding cycle we have found that changes in inter-filament spacing is not the mechanism that underlies LDA. Furthermore, we discovered that cardiac troponin-I is essential for LDA. Preliminary studies now show that interruption of cooperative activation along the thin filament markedly enhances LDA, while a reduction in active cycling cross-bridges does not affect LDA. Together, our findings suggest that the molecular mechanisms that underlie length dependency in muscle are the result of a direct sarcomere length mediated modulation of the structure/function of the thin filament system, myosin and/or thick filament system, or the kinetics/structure of the interaction between actin and myosin. The proposed research project is focused around three specific aims to test whether LDA is the result of modulation at the level of the thin filament, the thick filament or the kinetics of actin-myosin interaction. Overall, we have obtained preliminary data that demonstrate the feasibility of our hypotheses as well as our technical expertise to conduct the proposed experiments. Although the Frank- Starling Law of the Heart constitutes a fundamental property of the heart that has been appreciated for well over a century, the molecular mechanisms that underlie this phenomenon are still incompletely understood. Our research proposal is aimed to enhance our understanding of this important physiological process that controls cardiac performance on a beat-to-beat basis. PUBLIC HEALTH RELEVANCE: The Frank-Starling Law describes the fundamental property of the heart to increase cardiac strength in response to increased filling volume. The cellular mechanism for this phenomenon is an increase in myofilament Ca2+ responsiveness in response to sarcomere stretch via mechanisms that are incompletely understood. We will employ isolated myocardium for biophysical measurements probing at thin and thick filament structure using contractile protein exchange, transgenic murine models, fluorescent probes, as well as x-ray diffraction. The overall aim is to unravel the molecular mechanisms that underlie this important physiological regulatory system operating in the heart on a beat-to- beat basis.

描述（由申请人提供）：弗兰克-斯塔林心脏定律描述了舒张末期容量和心脏射血量之间的相互关系，这是一种在逐次心跳基础上运行的调节系统。在细胞水平上，肌节长度 (SL) 依赖性肌丝 Ca2+ 敏感性是这种现象的基础（长度依赖性激活 -LDA）。收缩装置如何转换有关 SL 的信息尚不清楚。我们研究的总体目标是阐明 LDA 的分子机制。在上一个资助周期中，我们发现细丝间距的变化并不是 LDA 的机制。此外，我们发现心肌肌钙蛋白-I 对于 LDA 至关重要。现在的初步研究表明，沿着细丝的协同激活的中断显着增强了LDA，而活跃循环跨桥的减少并不影响LDA。总之，我们的研究结果表明，肌肉长度依赖性的分子机制是细丝系统、肌球蛋白和/或粗丝系统的结构/功能的直接肌节长度介导调节的结果，或肌动蛋白和肌球蛋白之间相互作用的动力学/结构的结果。拟议的研究项目集中于三个具体目标，以测试 LDA 是否是细丝、粗丝或肌动蛋白-肌球蛋白相互作用动力学水平调节的结果。总的来说，我们已经获得了初步数据，证明了我们的假设的可行性以及我们进行拟议实验的技术专长。尽管弗兰克-斯塔林心脏定律构成了心脏的基本特性，一个多世纪以来一直受到人们的重视，但这种现象背后的分子机制仍然不完全清楚。我们的研究计划旨在增强我们对这一重要生理过程的理解，该过程控制逐次心跳的心脏功能。公共健康相关性：弗兰克-斯塔林定律描述了心脏的基本特性，即随着充盈量的增加而增加心脏力量。这种现象的细胞机制是肌丝 Ca2+ 响应性增加，以响应肌节拉伸，但机制尚不完全清楚。我们将利用离体心肌进行生物物理测量，利用收缩蛋白交换、转基因小鼠模型、荧光探针以及 X 射线衍射来探测细丝和粗丝结构。总体目标是揭示心脏中逐次跳动运行的重要生理调节系统的分子机制。