and Specific Aims.) This application is part of a long-term effort to characterize the basic mechanisms underlying the airway remodeling that occurs in patients with chronic diseases of the airways. A key step in this process is identification of the molecular mechanisms by which airway epithelial cells interact with the extracellular matrix. Integrins represent the largest known family of receptors for extracellular matrix proteins, and the homology-based polymerase chain reaction has been used to identify novel subunits of integrins. The goals of the present application are to characterize the tissue distribution, matrix protein ligand(s), and cellular function(s) of integrins containing one of these subunits, a9, and to examine expression of these receptors in airway biopsies of healthy human subjects and subjects with asthma in the presence or absence of superimposed airway injury and inflammation.
The Specific Aims are to: 1) complete the full length deduced amino acid sequence of a9 and to demonstrate that it encodes an integrin protein; 2) to identify and characterize the apparently novel b subunit partner of a9 in airway epithelial cells; 3) determine the cell and tissue distribution of a9 integrins; 4) determine the ligand(s) for a9 integrins; 5) determine the effects of a9 integrins on cell behavior; and 6) determine the expression and distribution of a9 in normal and asthmatic human airways before and after injury and inflammation. The results may shed light on the general process of epithelial-matrix interactions, and could provide insight into the molecular mechanisms underlying the airway remodeling that characterizes airway disease such as asthma.
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