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量之间的相互关系，这是一个以搏动为基础的调节系统。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（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转导的，目前还不清楚。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。由于我们最近发现松弛肌肉中的丝间间距并不是LDA的基础，我们的第一个目标是检验这一假设，即在活动肌肉中获得的丝间间距是LDA的基础。其次，我们最近发现肌钙蛋白，特别是心肌肌钙蛋白- 1，在LDA中起着关键作用。因此，我们的第二个目标将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是否足以和/或需要向横纹肌传递LDA的假设；实验将在皮肤肌肉中进行重组蛋白提取-重建实验。总的来说，我们已经获得了初步的数据，证明了我们的假设的可行性，以及我们的技术专长来进行拟议的实验。尽管弗兰克-斯塔林心脏定律构成了心脏的基本属性，已经被人们认识了一个多世纪，但这一现象背后的分子机制仍然没有被完全理解。我们的研究计划旨在加强我们对这一重要生理过程的理解，这一生理过程控制着心脏在每一次跳动的基础上的表现。

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.