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

描述（由申请人提供）：平滑肌收缩是精细调节的，以执行其周围许多不同器官和脉管系统的特定机械功能。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则调整为优化呼吸。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哮喘相关的气道高反应性。因此，了解调节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凝蛋白分子产生的力。然而，单分子测量与肌肉总体力学行为之间的联系仍不清楚。具体来说，我们对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。一种弥合单个肌凝蛋白力学和整个肌肉力学之间的差距的方法是从其组成部分建立一个模型平滑肌系统。激光陷阱将再次在这项工作中发挥关键作用，它提供了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。基本的构建模块将是肌动蛋白和肌凝蛋白，最初的兴趣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。目标是使用生化分析、激光陷阱、先进成像技术、计算机和分析建模来确定平滑肌中肌球蛋白分子的力产生、力传递和力感知之间的相互作用如何有助于平滑肌在正常和疾病状态下收缩的机制。公共卫生相关性：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则调整为优化呼吸。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.