and specific aims): Airway smooth muscle is unique in that it is constantly subjected to stretch and retraction as lung volume changes during breathing. In normal individuals, deep inspiration results in a reduction in airway tone and in airway resistance. The stretch and retraction of airway smooth muscle during tidal breathing may also play an important role in limiting the constriction of the airways in response to a bronchoconstrictor. Recent data suggest that the airway hyperreactivity associated with asthma might result from abnormalities in the regulation of airway tone in response to changes in lung volume rather than from intrinsic differences in the sensitivity of airway smooth muscle to bronchoconstrictors. The long term goal of this project is to determine the cellular mechanisms which regulate airway smooth muscle tone under the dynamic conditions present during breathing.
The specific aims are to: 1) determine whether the development of active tension in airway smooth muscle is associated with phosphorylation of MADP cytoskeletal proteins; 2) determine the signalling pathways which regulate the phosphorylation of MADP cytoskeletal proteins in airway smooth muscle; 3) determine whether the contractile activation of smooth muscle is associated with changes in the cellular localization of MADP cytoskeletal proteins or the kinases which activate them; and 4) develop physiologic approaches for the assessment of functional properties of airway smooth muscle which are sensitive to cytostructural modifications.
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