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

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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.