Bioengineering Analysis of Muscle Mechanics & Metabolism

肌肉力学的生物工程分析

• 批准号: 7064230
• 负责人: SRBOLJUB M MIJAILOVICH
• 金额: $ 56.2万
• 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/7064230
• 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）： 使用工程分析的方法，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的知识来描述肌肉收缩。我们的目标是开发一个全面的模型，可用于（1）产生新的机制假说的收缩蛋白肌球蛋白和肌动蛋白的功能和（2）定量评估的作用，辅助和调节蛋白在收缩。一旦开发出来，该模型将成为肌肉收缩研究中一个强大的分析和预测工具。目前，没有收缩模型解释由于（1）肌动蛋白和肌球蛋白丝的伸展性和（2）收缩的Ca 2+调节引起的并发症。细丝的可伸展性导致沿着粗细丝和细丝的不均匀载荷传递，这在肌球蛋白头与肌动蛋白相互作用期间引入了肌球蛋白头的应力和应变的可变性。必须考虑这些影响，以了解如何跨桥力影响肌动球蛋白ATP酶循环中的化学转换，反之亦然。此外，定量了解钙2+的调节将允许（1）更准确的预测宏观的机械和能量的后果，具体的监管活动和（2）更准确的解释宏观事件的基础分子过程。这个BRP通过跨工程科学，计算科学和生物物理学的多学科方法解决这些问题，并完全依赖于第一原则。我们的研究小组将开发一个收缩模型，该模型整合了一个关键的缺失元素--肌丝可伸展性--以及最近在以下方面的进展：（1）肌球蛋白的生化状态;（2）肌动球蛋白ATP水解循环中的过渡速率常数;（3）肌球蛋白分子马达在粗细肌丝晶格（肌节）中的功能;以及（4）肌球蛋白结合的Ca 2+调节。最初，该模型将结合联合收割机概率或随机肌动球蛋白结合动力学与有限元分析（连续或空间离散一致的周期性的厚和薄的细丝）。然后，该模型将被细化，以解释平滑肌收缩，包括能量有效的闩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则，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和心力衰竭中的心脏和骨骼肌无力。