Chemical-induced acute lung injury (CIALI) can result from numerous chemical threats that avail themselves to terrorist attacks. Therapies are needed to treat the acute effects and pathologies that are common to several chemical threat agents. Despite intensive effort, much remains to be understood regarding pathological events linking Inhalation exposures to delayed pulmonary edema, respiratory failure, and ultimately death. In past funding period we developed and validated mouse models of acute lung injury to 5 common chemicals (acrolein, ammonia, chlorine, phosgene, and sulfuric acid). Using a functional genomics approach, 40 mouse strains were used to identify candidate genes associated with survival time following exposure. We combined the results to build a protein interaction network (interactome). Within this network, a cell signaling hub (i.e. a protein with several protein-protein interactions) was uncovered that implicated v- AKT1 thymoma viral oncogene homolog 1 (AKT1). When phosphorylated, AKT1 enhances survival by inactivating components of the cell death machinery. Although undesirable in cancer, we reasoned that short-term, reversible enhancement of the cell survival AKT1 activity could be beneficial in CIALI treatment. We subsequently found that inhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a phosphatase that limits AKT1 activity, enhances epithelial repair in vitro and protect against CIALI in vivo. Hypothesis: Inhibition of PTEN activity will impart resistance to CIALI by activating signaling events that promote cell survival. Approach: Using a high content screening method, lead compounds [including a PTEN inhibitor] will be administered in vitro to test reverse of lethality in target cells. Lead compounds will be tested in mouse models of lethality from CIALI with 5 chemicals. Overall Objective: To develop a therapy that improves survival during lung injury induced by multiple chemicals. Public Health Relevance: Acute lung injury can result from numerous chemical threats that avail themselves to terrorist attacks. Current therapy remains limited to supportive care with no approved therapeutic for post insult treatment. The overall objective is to develop a therapy that will improve survival during acute lung injury induced by more than one chemical.
| George, Leema; Mitra, Ankita; Thimraj, Tania A et al. (2017) Transcriptomic analysis comparing mouse strains with extreme total lung capacities identifies novel candidate genes for pulmonary function. Respir Res 18:152 |
| Latoche, Joseph D; Ufelle, Alexander Chukwuma; Fazzi, Fabrizio et al. (2016) Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice. Environ Health Perspect 124:1199-207 |
| Moon, Kuk-Young; Lee, Pureun-Haneul; Kim, Byeong-Gon et al. (2015) Claudin 5 in a murine model of allergic asthma: Its implication and response to steroid treatment. J Allergy Clin Immunol 136:1694-1696.e5 |
| Coon, Tiffany A; McKelvey, Alison C; Weathington, Nate M et al. (2014) Novel PDE4 inhibitors derived from Chinese medicine forsythia. PLoS One 9:e115937 |
| Moon, Kuk-Young; Park, Moo-Kyun; Leikauf, George D et al. (2014) Diesel exhaust particle-induced airway responses are augmented in obese rats. Int J Toxicol 33:21-8 |
| Brant, Kelly A; Leikauf, George D (2014) Dysregulation of FURIN by prostaglandin-endoperoxide synthase 2 in lung epithelial NCI-H292 cells. Mol Carcinog 53:192-200 |
| Ganguly, Koustav; Martin, Timothy M; Concel, Vincent J et al. (2014) Secreted phosphoprotein 1 is a determinant of lung function development in mice. Am J Respir Cell Mol Biol 51:637-51 |
| Fazzi, Fabrizio; Njah, Joel; Di Giuseppe, Michelangelo et al. (2014) TNFR1/phox interaction and TNFR1 mitochondrial translocation Thwart silica-induced pulmonary fibrosis. J Immunol 192:3837-46 |
| Bein, Kiflai; Di Giuseppe, Michelangelo; Mischler, Steven E et al. (2013) LPS-treated macrophage cytokines repress surfactant protein-B in lung epithelial cells. Am J Respir Cell Mol Biol 49:306-15 |
| Leikauf, George D; Concel, Vincent J; Bein, Kiflai et al. (2013) Functional genomic assessment of phosgene-induced acute lung injury in mice. Am J Respir Cell Mol Biol 49:368-83 |
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