Stretch of the airways caused by tidal breathing and deep inspiration plays an important role in the regulation of normal airway responsiveness. The effects of stretch on airway smooth muscle tone result from mechanical properties of the muscle that are not explained by traditional sliding filament models of smooth muscle contraction: The contractile responses of airway muscle are not fixed for any particular set of stimulation conditions; the muscle adapts its contractile behavior in response to its mechanical environment. A novel model for airway smooth muscle contraction that can account for these mechanical properties is proposed in which active tension generation requires two parallel processes: the activation of contractile proteins leading to crossbridge cycling, and the active remodeling and anchoring of actin filaments to the membrane for the transmission of force from the contractile apparatus to the extracellular matrix. Mechanical strain is proposed to modulate cytoskeletal organization, thereby changing the organization of the contractile apparatus. It is proposed that transmembrane integrins sense mechanical strain and initiate signaling cascades that trigger the reorganization of cytoskeletal structure via actin filament remodeling and the modulation of their sites of membrane attachment. The focus of the current project is to determine the mechanisms by which mechanical stimuli are transduced and transmitted to the smooth muscle cytoskeleton, and the effect of these signaling pathways on contractile protein activation and cytoskeletal structure. Experiments will be performed using trachealis muscle strips in vitro, in which cytoskeletal mechanisms are ecaluated following interventions that target the specific molecular interactions of cytoskeletal proteins.
The specific aims of proposal are: 1.) Evaluate the molecular mechanisms for the transmission of tension between the contractile apparatus and the extracellular matrix in airway smooth muscle. 2.) Evaluate the roles of the signaling molecules focal adhesion kinase and paxillin in pathways regulating the activation of contractile proteins and cytoskeletal organization in tracheal smooth muscle tissues. 3.) Evaluate molecular mechanisms that contribute to the mechanosensitive regulation of contractile function in tracheal smooth muscle. These studies will provide evidence for important new signaling pathways and novel mechanisms for the regulation of smooth muscle contractility. These concepts provide a framework for understanding how the contractility and functional properties of airway smooth muscle are regulated under dynamic conditions that occur during breathing.
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