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

弗兰克-斯塔林心脏定律：细胞机制

• 批准号: 7452409
• 负责人: Pieter P. de TOMBE
• 金额: $ 0.49万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7452409
• 关键词: Adrenergic Agents; Binding; Cardiac; Cardiac Volume; Charge; Complex; Contracts; Data; Development; Filament; Gene Transfer Techniques; Goals; Heart; Ions; Lead; Length; Mannitol; Measurement; Measures; Microfilaments; Molecular; Mus; Muscle; Muscle Contraction; Mutation; Myocardium; Operating System; Performance; Phosphorylation; Physiological Processes; Play; Probability; Property; Protein Isoforms; Protein Kinase; Recombinant Proteins; Recombinants; Research; Research Personnel; Research Project Grants; Research Proposals; Role; Sarcomeres; Series; Signal Transduction; Skeletal Muscle; Skeletal system; Skin; Starling (law); Striated Muscles; Technical Expertise; Testing; Thick; Thin Filament; Time; Troponin; Troponin C; Troponin I; Variant; adrenergic; base; programs; protein protein interaction; reconstitution; research study; theories

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.

描述（由申请人提供）：心脏坦率的坦率定律描述了末期 - 舒张量和心脏射血量之间的相互关系，这是一种调节系统，以节拍为基础。在细胞水平上，肌膜长度（SL）依赖性肌丝Ca2+灵敏度是这种现象（长度依赖性激活-LDA）的基础。肌肉的收缩仪如何传递有关SL的信息的信息是众所周知的。我们研究的总体目标是阐明LDA构成的分子机制。拟议的研究项目集中在两个具体目标围绕。由于我们最近发现，放松的肌肉中的丝间间距不是LDA的基础，因此我们的第一个目的是检验以下假设，即它是在LDA构成的活性肌肉中获得的丝间间距。其次，我们最近发现肌钙蛋白，尤其是心脏肌钙蛋白L，在LDA中起关键作用。因此，在我们的第二个目标中，将决定肌细胞素和合作激活在肌丝长度依赖性激活中的作用。我们将检验以下假设：心脏肌钙蛋白足够和/或需要在条纹肌肉上赋予LDA。实验将使用皮肤肌肉中的重组蛋白提取恢复实验进行。总体而言，我们获得了初步数据，这些数据证明了我们的假设的可行性以及我们的技术专业知识来进行拟议的实验。尽管心脏的坦率坦率定律构成了心脏的基本特性，它在一个多世纪以来都受到赞赏，但仍未完全理解这种现象的分子机制。我们的研究建议旨在增进我们对这一重要生理过程的理解，该过程以节奏控制心脏表现以击败基础。