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

描述（由申请人提供）：心脏的Frank-Starling定律描述了舒张末期容积和心脏射血容积之间的相互关系，这是一种在逐搏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Ca 2+敏感性是这种现象（长度依赖性激活-LDA）的基础。收缩器如何转换有关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。在上一个融资周期中，我们发现灯丝间距的变化并不是LDA的基础机制。此外，我们发现心肌肌钙蛋白-I是LDA所必需的。初步研究表明，合作激活沿着细灯丝中断显着提高LDA，而减少积极的循环跨桥不影响LDA。总之，我们的研究结果表明，肌肉中的长度依赖性的分子机制是直接肌节长度介导的细丝系统，肌球蛋白和/或粗丝系统的结构/功能的调节，或肌动蛋白和肌球蛋白之间的相互作用的动力学/结构的结果。拟议的研究项目集中在三个具体目标，以测试LDA是否是在细丝，粗丝或肌动蛋白-肌球蛋白相互作用的动力学水平上调制的结果。总体而言，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。尽管心脏的弗兰克-斯塔林定律构成了心脏的基本特性，已经被欣赏了超过世纪，但这种现象背后的分子机制仍然没有完全理解。我们的研究计划旨在提高我们对这一重要生理过程的理解，该过程控制心脏的逐搏性能。公共卫生相关性：Frank-Starling定律描述了心脏的基本性质，即增加心脏力量以响应增加的充盈量。这种现象的细胞机制是肌丝Ca 2+响应性通过不完全理解的机制响应肌节拉伸而增加。我们将采用分离的心肌进行生物物理测量，使用收缩蛋白交换、转基因小鼠模型、荧光探针以及X射线衍射来探测薄和厚的细丝结构。总的目标是解开这个重要的生理调节系统在心脏跳动的基础上运作的分子机制。

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.