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

描述(由申请人提供)：平滑肌肉收缩是微调的，以执行特定于许多不同器官和它们周围的血管系统的机械功能。例如，血管平滑肌的特定张力控制血压，而呼吸道平滑肌的缩短则调节以优化呼吸。平滑肌细胞收缩行为的改变可导致多种病理生理状态，如高血压导致心力衰竭和与哮喘相关的呼吸道高反应性。因此，关于调节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都是至关重要的。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。具体地说，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一个模型肌肉系统。激光陷阱将再次在这一努力中发挥关键作用，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机械效应。基本的构件将是肌动蛋白和肌球蛋白，最初感兴趣的是模型肌肉系统中的力产生机制、力传递机制和力感知机制。其目标是使用生化分析、激光陷阱、先进的成像技术以及计算机和分析建模来确定在正常和疾病状态下，肌球蛋白分子的力产生、力传递和力感知之间的相互作用是如何促进平滑肌肉收缩的机制。与公共健康相关：平滑肌收缩被微调，以执行特定于其周围许多不同器官和血管系统的机械功能。例如，血管平滑肌的特定张力控制血压，而呼吸道平滑肌的缩短则调节以优化呼吸。平滑肌细胞收缩行为的改变可导致多种病理生理状态，如高血压导致心力衰竭和与哮喘相关的呼吸道高反应性。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。

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.