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: 8320624
• 负责人: Pieter P. de TOMBE
• 金额: $ 7.36万
• 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/8320624
• 关键词: Actins; Adopted; Affect; Binding; Cardiac; Cardiac Volume; Contractile Proteins; Data; Dependency; Filament; Fluorescent Probes; Funding; Goals; Grant; Head; Health; 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 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; 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）：心脏坦率的坦率定律描述了末期 - 舒张量和心脏射血量之间的相互关系，这是一种以节拍对基础运行的监管系统。在细胞水平上，肌膜长度（SL）依赖性肌丝Ca2+灵敏度是这种现象（长度依赖性激活-LDA）的基础。收缩设备如何传递有关SL的信息的传递方式尚不清楚。我们研究的总体目标是阐明LDA构成的分子机制。在上一个融资周期中，我们发现丝间间距的变化不是LDA构成的机制。此外，我们发现心脏肌钙蛋白I对于LDA至关重要。现在的初步研究表明，沿细丝的合作激活的中断显着增强了LDA，而主动循环跨支架的减少并不影响LDA。总之，我们的发现表明，肌肉长度依赖性的分子机制是薄丝细丝系统，肌球蛋白和/或厚丝系统的结构/功能的直接肌节长度介导的调节的结果，或肌动蛋白和肌球蛋白之间相互作用的动力学/结构。拟议的研究项目集中在三个特定目的围绕测试LDA是否是薄丝纤维，厚丝或肌动蛋白 - 肌球蛋白相互作用动力学的调节的结果。总体而言，我们获得了初步数据，这些数据证明了我们的假设的可行性以及我们的技术专业知识来进行拟议的实验。尽管心脏的坦率八个世纪以来一直受到赞赏的心脏的基本特性，但基于这种现象的分子机制仍然尚不完全理解。我们的研究建议旨在增强我们对这一重要的生理过程的理解，该过程以节拍对基础来控制心脏表现。公共卫生相关性：坦率的规律描述了心脏的基本属性，以增加心脏力量，以响应增加的填充量。这种现象的细胞机制是肌丝Ca2+响应性的增加，响应于肌节的响应，通过未完全理解的机制。我们将使用收缩蛋白质交换，转基因鼠模型，荧光探针以及X射线衍射，利用孤立的心肌进行生物物理测量探测的生物物理测量。总体目的是阐明这种重要的生理调节系统在心脏中运行的重要生理调节系统的基础。