This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Project 3: Smooth muscle cells 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. Altered contractile states of smooth muscle cells are the proximal cause of pathophysiological states such as hypertension resulting in cardiac failure and airway hyperresponsiveness associated with asthma, and the pathogenesis of these diseases involves smooth muscle remodeling in response to extended feedback between the contractile and signaling components of smooth muscle. Yet the contractile component remains something of a black box in models of smooth muscle remodeling and disease, in part because the molecular details of smooth muscle contraction and the interplay between force-generating and force-sensing mechanisms are not well understood. Smooth muscle generates force and movement through the smooth muscle actin-myosin ATPase reaction. But in addition to generating force and movement, smooth muscle myosins also sense force, modifying their biochemical kinetics in response to the forces they generate. The interplay between smooth muscle myosin?s force-generating and force-sensing mechanisms is thought to play a critical role in tuning the mechanical properties of smooth muscle and has been implicated in the economic tonic contractions of smooth muscle often referred to as latch. Yet remarkably little is known about how the forces generated by one myosin molecule are transmitted and cooperatively affect the biochemical kinetics of neighboring myosin molecules in smooth muscle. The goal of this project is to use state-of-the-art fluorescence microscopy and laser traps to characterize the interplay between smooth muscle myosin?s force-generating and force-sensing mechanisms as a prerequisite for determining the molecular basis for the unique mechanical properties of smooth muscle in normal and hypercontractile states.
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