This is a competitive renewal application to study the mechanisms whereby the epithelial integrin avb6 regulates pulmonary inflammation and fibrosis as well as airway remodeling. The investigators have shown that a homozygous null mutation of the b6 subunit gene leads to an accumulation of activated macrophages and lymphocytes in the lungs and airways of affected mice and to induction of the macrophage metalloelastase (MME) gene, yet the mice are protected from bleomycin-induced pulmonary fibrosis. Having shown that avb6 binds to a specific sequence within the latency-associated protein (LAP) of TGFb1, the investigators propose to use the b6 subunit knockout mouse (b6-/-) model to study the in vivo role of avb6 in lung inflammation and fibrosis. There are 3 specific aims.
The first aim i s to determine the role of TGFb1 activation in the induction of lung inflammation and protection from pulmonary fibrosis in beta6-/- mice. For this, transgenic mice expressing full-length and mutant forms of the b6 subunit will be used to determine whether TGFb1 activation or other effects of avb6 can prevent lung inflammation or induce pulmonary fibrosis. Also, they will evaluate whether avb6 acts upstream or downstream of TGFb1 activation, by infecting wild type and b6-/- mice with adenoviruses expressing either active or latent TGFb1 or transgenes that are considered to induce pulmonary fibrosis by acting upstream of TGFb.
The second aim i s to determine the significance of MME induction in the beta-/- phenotype. For this purpose, they will examine macrophage phenotypic features of double knockout (MME-/- b6-/-) mice generated by cross breeding of MME-/- and b-/- mice.
The third aim i s to determine the role of avb6 induction in airway remodeling. This will be accomplished by cross breeding b6-/- mice with transgenic mice that develop sub-epithelial fibrosis due to overexpression of IL-6, IL-11 or IL-13.
| 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 |
| 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 |
| Erle, David J; Sheppard, Dean (2014) The cell biology of asthma. J Cell Biol 205:621-31 |
| 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 |
| Friedman, Scott L; Sheppard, Dean; Duffield, Jeremy S et al. (2013) Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 5:167sr1 |
| Sheppard, Dean (2013) ROCKing pulmonary fibrosis. J Clin Invest 123:1005-6 |
| Henderson, Neil C; Arnold, Thomas D; Katamura, Yoshio et al. (2013) Targeting of ?v integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 19:1617-24 |
Showing the most recent 10 out of 55 publications
