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。关于SL的信息是如何通过肌肉的收缩装置来传递的，这是众所周知的。我们研究的总体目标是阐明LDA的分子机制。拟议的研究项目主要围绕两个具体目标。由于我们最近发现，在一个放松的肌肉中的细丝间的间距并不构成LDA的基础，我们的第一个目标是测试的假设，它是在一个活跃的肌肉，LDA的基础上获得的细丝间的间距。其次，我们最近发现肌钙蛋白，特别是心肌肌钙蛋白-l，在LDA中起着关键作用。因此，我们的第二个目标是确定肌钙蛋白和协同激活在肌丝长度依赖性激活中的作用。我们将检验心肌肌钙蛋白足以和/或需要在横纹肌上赋予LDA的假设;将在去皮肌肉中使用重组蛋白提取-重构实验进行实验。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Frank-Starling定律构成了心脏的基本性质，并且已经被认识了超过世纪，但是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，该过程控制心脏的跳动。

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 information concerning SL is transduced by the contractile apparatus of muscle is hot known. The overall goal of our research is to elucidate the molecular mechanisms that underlie LDA. The proposed research project is focused around two specific aims. Since we have recently found that inter-filament spacing in a relaxed muscle does not underlie LDA, our first aim is to test the hypothesis that it is inter-filament spacing attained in an active muscle that underlies LDA. Second, we have recently found that troponin, and particularly cardiac troponin-l, plays a pivotal role in LDA. Therefore, in our second aim will determine the role of troponin and cooperative activation in myofilament length dependent activation. We will test the hypothesis that cardiac troponin is sufficient and/or required to impart LDA upon a striated muscle; experiments will be performed using recombinant protein extraction-reconstitution experiments in skinned muscle. 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.