Bioengineering Analysis of Muscle Mechanics & Metabolism

肌肉力学的生物工程分析

• 批准号: 6790505
• 负责人: SRBOLJUB M MIJAILOVICH
• 金额: $ 53.58万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790505
• 关键词: actins; adenosinetriphosphatase; bioengineering /biomedical engineering; biomechanics; biophysics; calcium flux; computer simulation; laboratory rabbit; laboratory rat; model design /development; muscle contraction; muscle function; muscle metabolism; myosins; protein binding; sarcomeres; smooth muscle; thermodynamics

DESCRIPTION (provided by applicant): Using the methods of engineering analysis, we will develop a computational platform that incorporates current knowledge of molecular structure, biochemical energetics, and contraction kinetics to describe muscle contraction. Our goal is to develop a comprehensive model that can be used to (1) generate new mechanistic hypotheses concerning the functions of the contractile proteins myosin and actin and (2) quantitatively evaluate the roles of accessory and regulatory proteins in contraction. Once developed, the model will be a powerful analytical and predictive tool in studies of muscle contraction. Presently, no models of contraction account for complications due to both (1) extensibility of the actin and myosin filaments and (2) Ca2+ regulation of contraction. Filament extensibility results in non-uniform load transfer along the thick and thin filaments, which introduces variability in the stress and strain of the myosin heads during their interactions with actin. These effects must be taken into account to understand how cross-bridge forces affect chemical transitions in the actomyosin ATPase cycle and vice versa. Further, quantitative understanding of Ca 2+ regulation will allow (1) more accurate predictions of the macroscopic mechanical and energetic consequences of specific regulatory events and (2) more accurate explanations of macroscopic events in terms of underlying molecular processes. This BRP addresses these problems via a multidisciplinary approach that spans engineering science, computational science, and biophysics and rests entirely upon first principles. Our team will develop a model of contraction that integrates a critical missing element-filament extensibility-with recent advances in understanding the (1) biochemical states of myosin; (2) transitional rate constants in the actomyosin ATP hydrolysis cycle; (3) function of myosin molecular motors in the thick and thin filament lattice (sarcomere); and (4) Ca 2+ regulation of myosin binding. Initially, the model will combine probabilistic or stochastic actomyosin binding kinetics with finite element analysis (either continuous or spatially discrete consistent with the periodicities of the thick and thin filaments). The model will then be refined to explain smooth muscle contraction, including the energetically efficient latch state and the actions of proteins involved in the regulation of contraction. The computational model developed here will invoke unifying principles that apply to the actomyosin interaction cycle regardless of muscle type but will have sufficient flexibility to account for contraction kinetics and regulation of contraction in different muscle types. Quantitative modeling of contraction is ultimately essential for understanding the molecular basis for a wide range of syndromes and diseases, such as airway narrowing in asthma and weakness of both heart and skeletal muscles in heart failure.

描述（由申请人提供）： 使用工程分析方法，我们将开发一个计算平台，结合当前的分子结构、生化能量学和收缩动力学知识来描述肌肉收缩。我们的目标是开发一个综合模型，可用于（1）生成有关收缩蛋白肌球蛋白和肌动蛋白功能的新机制假设，以及（2）定量评估辅助蛋白和调节蛋白在收缩中的作用。一旦开发出来，该模型将成为肌肉收缩研究中强大的分析和预测工具。目前，还没有收缩模型能够解释由于 (1) 肌动蛋白和肌球蛋白丝的可伸展性以及 (2) Ca2+ 收缩调节引起的并发症。肌丝延伸性导致沿粗丝和细丝的负载传递不均匀，从而导致肌球蛋白头在与肌动蛋白相互作用期间的应力和应变发生变化。必须考虑这些影响，以了解跨桥力如何影响肌动球蛋白 ATP 酶循环中的化学转变，反之亦然。此外，对Ca 2+ 调节的定量理解将允许（1）更准确地预测特定调节事件的宏观机械和能量后果，以及（2）根据潜在的分子过程更准确地解释宏观事件。该 BRP 通过跨学科方法解决这些问题，涵盖工程科学、计算科学和生物物理学，并完全基于首要原则。我们的团队将开发一种收缩模型，该模型将关键的缺失元素（丝延伸性）与了解（1）肌球蛋白的生化状态的最新进展相结合； (2) 肌动球蛋白 ATP 水解循环中的过渡速率常数； (3)粗细丝晶格(肌节)中肌球蛋白分子马达的功能； (4)肌球蛋白结合的Ca 2+ 调节。最初，该模型将概率或随机肌动球蛋白结合动力学与有限元分析（连续或空间离散，与粗丝和细丝的周期性一致）相结合。然后，该模型将被完善以解释平滑肌收缩，包括能量有效的闭锁状态和参与收缩调节的蛋白质的作用。这里开发的计算模型将调用适用于肌动球蛋白相互作用周期的统一原理，无论肌肉类型如何，但将具有足够的灵活性来解释不同肌肉类型的收缩动力学和收缩调节。收缩的定量建模对于理解各种综合征和疾病的分子基础至关重要，例如哮喘中的气道狭窄以及心力衰竭中的心脏和骨骼肌无力。