This competitive renewal application is to continue on-going studies of the functions of the epithelial integrin, alphavbeta6. Based on analysis of beta6 knockout mice, alphavbeta6 plays a critical role in regulating pulmonary responses to injury through spatially and temporally regulated activation of the cytokine, transforming growth factor beta (TGFbeta). Alphavbeta6-mediated TGFbeta-activation is required for induction of pulmonary edema and pulmonary fibrosis in response to bleomycin, and homeostatically regulates macrophage protease expression, protecting the lungs from protease-mediated emphysema. Lung injury increases expression of alphavbeta6, but multiple lines of evidence suggest that under resting conditions alphavbeta6 is expressed but does not activate TGFbeta, and that alphavbeta6-mediated TGFbeta-activation is itself """"""""activated"""""""" by extracellular signals. The studies proposed in this application will address the critical question of how this process is regulated. Preliminary evidence suggests that known downstream targets of integrin signaling, the focal adhesion kinase (FAK) and the small GTPases, Rac1 and RhoA activate this pathway in a model culture system. Furthermore, IL-1beta, a toll-like/IL-1 receptor (TIR) ligand, activates this process in polarized alveolar and airway epithelial cells. We will therefore determine the range of TIR ligands involved, the roles of known components of the TIR signaling pathway, and how this pathway connects to FAK, Rac1 and RhoA. Preliminary results suggest that at least one structural alteration in the beta6 subunit, that mimics a mutant known to """"""""activate"""""""" integrins in leukocytes and platelets, also enhances alphavbeta6-mediated TGFbeta-activation. We will therefore examine a series of beta6 mutants targeting each of the steps associated with conformation-dependent activation of integrins on non-adherant cells to determine the extent to which activation of alphavbeta6-mediated TGFbeta-activation mimics this process of """"""""inside-out"""""""" conformational change of other integrins. Finally, we will utilize lines of mice already available to us expressing null mutations of components of the TIR signaling pathway, and mice we will generate predicted to either inducibly activate this pathway in alveolar epithelial cells or inducibly express maximally """"""""activated"""""""" integrin, to examine the relevance of our in vitro findings to each of the in vivo roles we have identified for alphavbeta6. The proposed studies should provide important general insights into the mechanisms underlying affinity and avidity modulation of integrins in adherant cells. They should also identify important targets that could be used to design treatments to intervene in acute lung injury, pulmonary fibrosis and emphysema.
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