The effects of stretch and oscillation on airway smooth muscle that occur normally during breathing are important in maintaining a normal low level of airway reactivity. The plasticity of the cytoskeletal structure of the airway smooth muscle cell may be fundamental to its ability to modulate its contractile and mechanical properties in response to the mechanical forces imposed on it in the lung. Integrin-linked kinase (ILK) is a multidomain (1-integrin-cytoplasmic domain binding protein and a functional serine-threonine protein kinase that associates with ( integrins and other cytoskeletal proteins at adhesion sites. The ILK protein complex is positioned to regulate structural links between integrin proteins and the actin cytoskeleton and to coordinate signaling pathways that regulate cytoskeletal functions. ILK has also been identified as a pivotal effecter in the transduction of signals from integrin proteins and the extracellular matrix to the nucleus. The proposed studies will evaluate the role of the ILK protein complex in regulating cytoskeletal organization and functional responses to the contractile stimulation of airway smooth muscle. The role of ILK in regulating the phenotype of airway smooth muscle will also be determined. Endogenous and recombinant protein expression will be manipulated in isolated tracheal smooth muscle tissues by transfecting tissues with plasmids encoding mutant forms of ILK and its binding partners and downstream effectors.
The specific aims are: 1) Determine whether the contractile stimulation of airway smooth muscle regulates the formation of an integrin-linked kinase (ILK) protein complex associated with sites of integrin adhesion to the extracellular matrix, and evaluate the function of this complex in the regulation of active tension generation. 2) Evaluate the effect of contractile stimulation on the kinase activity of ILK, and determine the role of ILK kinase activity in the regulation of tension development in airway smooth muscle. 3) Evaluate the role of the integrin-linked kinase protein complex in the regulation of protein synthesis and the expression of phenotypic proteins in airway smooth muscle tissues. The results will provide new information on the molecular mechanisms by which hormones and environmental stimuli regulate the structure and contractile responses of airway smooth muscle. This information will be important for understanding the pathogenesis of inflammatory diseases of the airways such as asthma.
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