Bioengineering Analysis of Muscle Mechanics & Metabolism

肌肉力学的生物工程分析

基本信息

批准号：
7230547
负责人：
SRBOLJUB M MIJAILOVICH
金额：
$ 55.53万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7230547
关键词：
ATP Hydrolysis Accounting Actins Actomyosin Actomyosin Adenosinetriphosphatase Address Affect Asthma Australia Behavior Binding Biochemical Biochemical Energetics Biochemistry Biomedical Engineering Biophysics Calcium Cell model Cells Chemicals Collaborations Computational Science Computer Analysis Computer Simulation Contractile Proteins Contractile System Data Disease Elements Engineering Event Filament Finite Element Analysis Generations Goals Head Heart Heart failure Kinetics Knowledge Link Mechanics Metabolism Methodology Methods Modeling Molecular Molecular Motors Molecular Structure Mosses Motor Muscle Muscle Contraction Muscle function Myocardium Myosin ATPase Organ Periodicity Phosphorylation Physiological Physiology Pliability Preparation Process Property Protein Dephosphorylation Protein Dynamics Proteins Publishing Range Rate Regulation Relaxation Research Research Personnel Rest Role Sarcomeres Science Skeletal Muscle Skeletal system Slide Smooth Muscle Statistical Models Stress Striated Muscles Structure Syndrome System Technology Testing Thermodynamics Thick Thick Filament Thin Filament Thinking Tissues Universities Update Wisconsin actin 2 base concept design genetic regulatory protein interdisciplinary approach novel programs research study theories tool

项目摘要

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，该平台结合了当前有关分子结构，生化能量和收缩动力学的知识，以描述肌肉收缩。我们的目标是开发一个可用于（1）有关收缩蛋白肌球蛋白和肌动蛋白功能的新机械假设的综合模型，以及（2）定量评估附件和调节蛋白在收缩中的作用。一旦开发，该模型将是肌肉收缩研究的强大分析和预测工具。目前，由于（1）肌动蛋白和肌球蛋白丝的可扩展性以及（2）CA2+收缩的调节，尚无收缩模型的并发症。丝的可扩展性导致沿厚和细丝的不均匀载荷转移，这在与肌动蛋白的相互作用过程中引入了肌球蛋白头部应力和应变的可变性。必须考虑这些影响，以了解跨桥力如何影响肌动蛋白ATPase周期中的化学转变，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）在基本分子过程中对宏观事件的更准确解释。该BRP通过跨越工程科学，计算科学和生物物理学的多学科方法来解决这些问题，并完全取决于第一原则。我们的团队将开发一种收缩模型，该模型整合了一个关键的缺失元素纹状体可扩展性，并在理解肌球蛋白的（1）生化状态方面取得了最新进展；（2）肌动蛋白ATP水解周期中的过渡速率常数；（3）在厚和薄丝晶格中肌球蛋白分子电动机的功能（肉瘤）；（4）肌球蛋白结合的Ca 2+调节。最初，该模型将结合概率或随机肌动蛋白结合动力学与有限元分析（连续或空间离散符合厚而薄丝的周期性）。然后，该模型将被改进以解释平滑肌收缩，包括能量有效的闩锁状态以及涉及调节收缩调节的蛋白质的作用。此处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说明收缩动力学和不同肌肉类型中收缩的调节。收缩的定量建模最终对于理解广泛的综合症和疾病的分子基础，例如哮喘的气道变窄以及心脏衰竭中心脏和骨骼肌的无力。