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.
| Mallavia, B; Liu, F; Sheppard, D et al. (2016) Inhibiting Integrin ?v?5 Reduces Ischemia-Reperfusion Injury in an Orthotopic Lung Transplant Model in Mice. Am J Transplant 16:1306-11 |
| Reed, Nilgun I; Jo, Hyunil; Chen, Chun et al. (2015) The ?v?1 integrin plays a critical in vivo role in tissue fibrosis. Sci Transl Med 7:288ra79 |
| Li, John T; Melton, Andrew C; Su, George et al. (2015) Unexpected Role for Adaptive ??Th17 Cells in Acute Respiratory Distress Syndrome. J Immunol 195:87-95 |
| Plaks, Vicki; Boldajipour, Bijan; Linnemann, Jelena R et al. (2015) Adaptive Immune Regulation of Mammary Postnatal Organogenesis. Dev Cell 34:493-504 |
| Xu, Pinglong; Bailey-Bucktrout, Samantha; Xi, Ying et al. (2014) Innate antiviral host defense attenuates TGF-? function through IRF3-mediated suppression of Smad signaling. Mol Cell 56:723-37 |
| Madala, Satish K; Korfhagen, Thomas R; Schmidt, Stephanie et al. (2014) Inhibition of the ?v?6 integrin leads to limited alteration of TGF-?-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 306:L726-35 |
| Erle, David J; Sheppard, Dean (2014) The cell biology of asthma. J Cell Biol 205:621-31 |
| Arnold, Thomas D; Niaudet, Colin; Pang, Mei-Fong et al. (2014) Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking ?V?8-TGF? signaling in the brain. Development 141:4489-99 |
| Henderson, Neil C; Sheppard, Dean (2013) Integrin-mediated regulation of TGF? in fibrosis. Biochim Biophys Acta 1832:891-6 |
| Su, George; Atakilit, Amha; Li, John T et al. (2013) Effective treatment of mouse sepsis with an inhibitory antibody targeting integrin *v*5. Crit Care Med 41:546-53 |
Showing the most recent 10 out of 33 publications
