TIME-RESOLVED X-RAY DIFFRACTION OF CARDIAC MUSCLE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。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，这是一种在逐个心跳的基础上运行的调节系统。在细胞水平上，肌节长度(SL)依赖肌丝的钙敏感性是这种现象(长度依赖的激活-LDA)的基础。关于SL的信息是如何通过肌肉的收缩装置传递的，目前尚不清楚。我们研究的总体目标是阐明LDA背后的分子机制。由于我们最近发现，放松肌肉中的细丝间距并不是LDA的基础，我们的第一个目标是检验这一假设，即是活跃肌肉中获得的微丝间距是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-L，在LDA中起着关键作用。因此，在我们的第二个目标中，将确定肌钙蛋白和协同激活在肌丝长度依赖激活中的作用。我们将验证这样的假设，即心肌肌钙蛋白足以和/或需要将LDA传递给横纹肌；结合X射线衍射和力学实验，将使用重组蛋白质提取-重建实验在皮肤肌肉中进行。尽管弗兰克-斯塔林心脏定律构成了心脏的一个基本性质，它已经被认识了一个多世纪，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加强我们对这一重要的生理过程的了解，这一过程在逐个心跳的基础上控制心脏性能。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 not known. The overall goal of our research is to elucidate the molecular mechanisms that underlie LDA. 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. Secondly, 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; combined X-ray diffraction and mechanical experiments will be performed using recombinant protein extraction-reconstitution experiments in skinned muscle. 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 plan is aimed to enhance our understanding of this important physiological process that controls cardiac performance on a beat to beat basis.