The mechanical stimulation of airway smooth muscle (ASM) that occurs during stretch and oscillation of the airways during breathing is critical for maintaining a normal low level of airway reactivity. Furthermore, chronic loading of the airways by continuous positive end expiratory pressure (CPAP) in vivo or prolonged loading of ASM in vitro reduces airway responsiveness and alters ASM phenotype, suggesting that CPAP may act as a potential therapy for asthma. Pathophysiologic conditions also induce alterations in mechanical forces imposed on the airways during breathing and in airway tissue structure and extracellular matrix composition. These environmental changes modulate ASM phenotype and its responses to physiologic stimuli, but the mechanisms for the effects of mechanical forces and the extracellular environment on the properties of ASM are not understood.The adhesion junctions that connect cells within tissues to the extracellular matrix are composed of large multiprotein complexes termed """"""""adhesomes"""""""". Adhesomes provide mechanical coupling between cells and their matrix environment, and they also enable cells to sense and respond to changes in their surrounding milieu. The contractile stimulation of ASM triggers the recruitment of structural and signaling proteins to adhesome complexes, and adhesome signaling complex components are critical for the normal physiologic responses of ASM to stimulation. However, the molecular mechanisms that catalyze adhesome assembly in response to ASM stimulation and regulate the organization and activation of component proteins are not known. The proposed studies will explore a novel molecular hypothesis for the assembly and activation of adhesome proteins in ASM in response to contractile and inflammatory stimuli. These processes are fundamental components of the signal transduction process in ASM, and provide a mechanism for ASM to integrate its physiologic responses to humoral and environmental stimuli. The proposed studies will employ ASM tissues and freshly dissociated differentiated ASM cells to address three Specific Aims: 1) Determine the roles of RhoA and NM myosin II in regulating the assembly and activation of adhesome signaling complexes, cytoskeletal dynamics and ASM contractility. 2) Determine how contractile stimulation regulates the activation of integrin adhesome complex proteins. 3) Determine the roles of RhoA, NM myosin II and adhesome protein activation in regulating the responses of ASM to inflammatory and humoral stimuli and their modulation by mechanical forces and extracellular matrix proteins. These studies will provide new insights into the molecular mechanisms of signal transduction in ASM that are likely to be broadly relevant to other cells and tissues, and are important for understanding how mechanical forces interact with drugs and hormones to regulate the physiologic responses in ASM tissues. They will provide a basis for designing new therapeutic approaches involving mechanical modalities as well as pharmacologic therapy for the treatment of airways disease.
The physiologic responses of airway smooth muscle to endogenous hormones and exogenous stimuli, including therapeutic agent, are affected by the external forces imposed on the airway tissues during breathing and the local environment of the cells. The project will describe new molecular processes by which airway smooth muscle integrates mechanical and local environmental stimuli with humoral stimuli to determine its physiologic responses and properties. These studies are important for understanding how mechanical forces interact with drugs and hormones to regulate the physiologic responses in airway smooth muscle tissues, and will provide a basis for designing new therapeutic approaches involving mechanical modalities as well as pharmacologic therapy for the treatment of airways disease.
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