TIME-RESOLVED X-RAY DIFFRACTION OF CARDIAC MUSCLE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。心脏的弗兰克-斯塔林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还不清楚。我们研究的总体目标是阐明LDA的分子机制。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验证在活动肌肉中获得的丝间间距是LDA的基础这一假设。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；结合x射线衍射和力学实验，在皮肤肌肉中进行重组蛋白提取-重构实验。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搏动的基础上的表现。

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.