A Multi-Scale Study of the Interplay Between Force Generating and Force Sensing M

力生成和力传感之间相互作用的多尺度研究

• 批准号: 8102983
• 负责人: Jonathan E. Baker
• 金额: $ 34.87万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102983
• 关键词: Accounting; Actin-Binding Protein; Actins; Affect; Asthma; Behavior; Binding; Biochemical; Biochemistry; Biological Assay; Biological Models; Biophysics; Computer Simulation; Computers; Data; Dependence; Disease; Etiology; Feedback; Free Energy; Friction; Generations; Goals; Head; Health; Heart failure; Hypertension; Imaging Techniques; In Vitro; Isometric Exercise; Kinetics; Knowledge; Laboratories; Lasers; Lead; Measurement; Measures; Mechanics; Microfilaments; Modeling; Molecular; Muscle; Muscle Cells; Muscle Contraction; Mutation; Myopathy; Myosin ATPase; Organ; Outcome; Physiology; Play; Property; Proteins; Respiration; Role; Rotation; Smooth Muscle; Smooth Muscle Myocytes; Smooth Muscle Myosins; Surface; System; Techniques; Technology; Testing; Vascular Smooth Muscle; airway hyperresponsiveness; arm; blood pressure regulation; cell motility; fluorescence imaging; genetic regulatory protein; inhibitor/antagonist; insight; interest; mathematical model; mechanical behavior; muscular system; reconstitution; respiratory smooth muscle; single molecule; small molecule; transmission process

DESCRIPTION (provided by applicant): Smooth muscle contractions are finely tuned to carry out mechanical functions specific to the many different organs and vasculature they surround. For instance, the specific tone of vascular smooth muscle controls blood pressure whereas the shortening of airway smooth muscle is tuned to optimize respiration. Changes in the contractile behaviors of smooth muscle cells can lead to a variety of pathophysiological states, such as hypertension resulting in cardiac failure and airway hyper responsiveness associated with asthma. Knowledge about the factors that contribute to tuning muscle mechanics is, therefore, critical for understanding both the molecular mechanism of smooth muscle contraction as well as the etiology of hyper reactive disease states. Recent advances in laser trap technology have allowed us to measure the forces generated by a single myosin molecule with remarkable accuracy. Nevertheless, the connection between single molecule measurements and the gross mechanical behaviors of muscle remains unclear. Specifically, we know remarkably little about how interactions among myosin molecules in muscle contribute to the emergent mechanical properties of muscle. One approach to bridging the gap between single myosin mechanics and whole muscle mechanics is to build up a model smooth muscle system from its constituent parts. Laser traps once again will play a critical role in this effort, providing a means of measuring the mechanics and biochemistry of a model system to determine the mechanical effects of each new component. The basic building blocks will be actin and myosin, and of initial interest are the mechanisms of force generation, mechanisms of force transmission and mechanisms of force sensing in the model muscle system. The goal is to use biochemical assays, laser traps, advanced imaging techniques, and computer and analytical modeling to determine how the interplay between force generation, force transmission, and force sensing by myosin molecules in smooth muscle contributes to the mechanics of smooth muscle contraction in normal and disease states. PUBLIC HEALTH RELEVANCE: Smooth muscle contractions are finely tuned to carry out mechanical functions specific to the many different organs and vasculature they surround. For instance, the specific tone of vascular smooth muscle controls blood pressure whereas the shortening of airway smooth muscle is tuned to optimize respiration. Changes in the contractile behaviors of smooth muscle cells can lead to a variety of pathophysiological states, such as hypertension resulting in cardiac failure and airway hyper responsiveness associated with asthma. Therefore, determining the factors that regulate muscle mechanics is critical for understanding the mechanisms of smooth muscle contraction and the etiology of hyper reactive disease states.

描述（由申请人提供）：平滑肌收缩被精细调节，以执行其周围许多不同器官和脉管系统特有的机械功能。例如，血管平滑肌的特定张力控制血压，而气道平滑肌的缩短被调整以优化呼吸。平滑肌细胞收缩行为的变化可导致多种病理生理状态，例如导致心力衰竭的高血压和与哮喘相关的气道高反应性。因此，了解有助于调整肌肉力学的因素对于理解平滑肌收缩的分子机制以及高反应性疾病状态的病因学至关重要。激光陷阱技术的最新进展使我们能够以惊人的精度测量单个肌球蛋白分子产生的力。然而，单分子测量和肌肉的总体力学行为之间的联系仍然不清楚。具体来说，我们对肌肉中肌球蛋白分子之间的相互作用如何影响肌肉的机械特性知之甚少。弥合单个肌球蛋白力学和整体肌肉力学之间的差距的一种方法是从其组成部分建立模型平滑肌系统。激光陷阱将再次在这项工作中发挥关键作用，提供一种测量模型系统的力学和生物化学的手段，以确定每个新组件的力学效应。基本的构建块将是肌动蛋白和肌球蛋白，并且最初感兴趣的是力产生的机制、力传递的机制和模型肌肉系统中的力感测的机制。目标是使用生化分析，激光陷阱，先进的成像技术，计算机和分析建模，以确定如何在平滑肌中的肌球蛋白分子的力产生，力传递和力传感之间的相互作用，有助于在正常和疾病状态下的平滑肌收缩的力学。公共卫生关系：平滑肌收缩被精细地调节以执行它们周围的许多不同器官和脉管系统特有的机械功能。例如，血管平滑肌的特定张力控制血压，而气道平滑肌的缩短被调整以优化呼吸。平滑肌细胞收缩行为的变化可导致多种病理生理状态，例如导致心力衰竭的高血压和与哮喘相关的气道高反应性。因此，确定调节肌肉力学的因素对于理解平滑肌收缩的机制和高反应性疾病状态的病因至关重要。

项目成果

Actin Sliding Velocities are Influenced by the Driving Forces of Actin-Myosin Binding.

肌动蛋白滑动速度受肌动蛋白-肌球蛋白结合驱动力的影响。

• DOI: 10.1007/s12195-013-0274-y
• 发表时间: 2013
• 期刊: Cellular and molecular bioengineering
• 影响因子: 2.8
• 作者: Stewart,TravisJ;JacksonJr,DelRay;Smith,RyanD;Shannon,StevenF;Cremo,ChristineR;Baker,JoshE
• 通讯作者: Baker,JoshE

Thermodynamics and Kinetics of a Binary Mechanical System: Mechanisms of Muscle Contraction.

• DOI: 10.1021/acs.langmuir.2c01622
• 发表时间: 2022-12-27
• 期刊: LANGMUIR
• 影响因子: 3.9
• 作者: Baker, Josh E.

The Problem with Inventing Molecular Mechanisms to Fit Thermodynamic Equations of Muscle.

• DOI: 10.3390/ijms242015439
• 发表时间: 2023-10-22
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Baker J

Cells solved the Gibbs paradox by learning to contain entropic forces.

• DOI: 10.1038/s41598-023-43532-w
• 发表时间: 2023-10-03
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Baker, Josh E.

Biochemistry of smooth muscle myosin light chain kinase.

• DOI: 10.1016/j.abb.2011.04.018
• 发表时间: 2011-06-15
• 期刊: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
• 影响因子: 3.9
• 作者: Hong, Feng;Haldeman, Brian D.;Jackson, Del;Carter, Mike;Baker, Jonathan E.;Cremo, Christine R.
• 通讯作者: Cremo, Christine R.