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

基本信息

批准号：
7904008
负责人：
Jonathan E. Baker
金额：
$ 33.49万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7904008
关键词：
Accounting Actin-Binding Protein Actins Affect Arts Asthma Behavior Binding Biochemical Biochemistry Biological Assay Biological Models Biophysics Computer Simulation Computers Data Dependence Disease Etiology Feedback Free Energy Friction Generations Goals Head 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 public health relevance reconstitution respiratory smooth muscle single molecule small molecule transmission process

项目摘要

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）：平滑肌收缩经过精心调整，以执行特定于它们所包围的许多不同器官和脉管系统的机械功能。例如，血管平滑肌的特定音调控制血压，而气道平滑肌的缩短则调节以优化呼吸。平滑肌细胞的收缩行为的变化会导致多种病理生理状态，例如高血压导致心力衰竭和与哮喘相关的气道超级反应性。因此，对有助于调整肌肉力学的因素的知识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至关重要。激光陷阱技术的最新进展使我们能够以明显的精度测量单个肌球蛋白分子产生的力。然而，单分子测量与肌肉总体机械行为之间的联系尚不清楚。具体而言，我们对肌肉肌球蛋白分子之间的相互作用如何促进肌肉的新机械性能。弥合单个肌球蛋白力学和整个肌肉力学之间差距的一种方法是从其组成部分建立模型平滑肌系统。激光陷阱再次将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方法，以确定每个新组件的力学效应。基本的构件将是肌动蛋白和肌球蛋白，最初感兴趣的是力产生的机制，力传播机制以及模型肌肉系统中力传感的机制。目的是使用生化测定，激光陷阱，高级成像技术以及计算机和分析建模来确定在平滑肌中，肌球蛋白分子在正常和疾病状态下，肌球蛋白分子在平滑肌中的产生，力传递和力传感之间的相互作用如何有助于平滑肌收缩的机制。公共卫生相关性：平滑肌肉收缩经过精心调整，以执行特定于它们所包围的许多不同器官和脉管系统的机械功能。例如，血管平滑肌的特定音调控制血压，而气道平滑肌的缩短则调节以优化呼吸。平滑肌细胞的收缩行为的变化会导致多种病理生理状态，例如高血压导致心力衰竭和与哮喘相关的气道超级反应性。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超反应性疾病状态的病因至关重要。