Acute lung injury has a poor prognosis and a diverse etiology. Numerous precipitating factors have been identified, yet questions remain about the pathophysiological mechanisms controlling this complex condition and their relationship to therapeutic strategies. Marked by epithelial damage and loss of surfactant function, acute lung injury can lead to growth factor activation, including activation of transforming growth factor-alpha (TGFalpha) and TGFbeta. These growth factors, in turn, control proliferation and the transcription of genes involved in differentiated function. Previously, a genetic locus that harbors TGFalpha was linked to, and TGFalpha transgenic mice were rescued from, acute lung injury. Additional data imply that these effects may be mediated through EGFR located on respiratory epithelial cells. Conditional TGFalpha transgenic mice have been generate to permit detailed investigations of the temporal role of this growth factor in lung injury. Recently, we found TGFbeta is released, and many TGFbeta responsive transcripts are altered in our model of acute lung injury. Our central hypothesis is that the interplay between TGFalpha and TGFbeta signaling pathways determines survival and the sequelae resulting from acute lung injury by altering transcriptional programs critical to lung function. To further assess the role of TGFalpha and TGFbeta in acute lung injury, we propose to manipulate TGFalpha signaling and monitor the consequences on TGFbeta signaling.
The Specific Aims of this proposal seek to: 1) Identify the molecular mechanisms responsible for TGFalpha/EGFR mediated protection in acute lung injury, 2) Evaluate the therapeutic efficacy of TGFalpha induction and TGFalpha/EGFR signaling during acute lung injury and determine whether pulmonary fibrosis is a necessary sequela as a consequence of protection, and 3) Determine the genetic mechanisms of TGFalpha and TGFbeta interactions that modulate critical gene expression, focusing on the cis-acting elements that control Sftpb promoter transactivation. This research is innovative because it will directly evaluate the potential therapeutic benefits of TGFalpha/EGFR signaling and the possible interactions of TGFalpha with TGFbeta in acute lung injury. At the completion of this project, we expect to: 1) Identify the transcriptional events modulated by TGFalpha that leads to protection from acute lung injury, 2) Gain a better understanding of how TGFbeta functions in acute lung injury, and 3) Determine whether pulmonary fibrosis is an untoward consequence of activating TGFalpha/EGFR signaling during acute lung injury. The anticipated impact of these studies would be an evidence-based scientific verification or refutation of the likelihood that therapeutics directed at TGFalpha/EGFR signaling could be considered for the treatment of acute lung injury.
| 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 |
| Coon, Tiffany A; McKelvey, Alison C; Weathington, Nate M et al. (2014) Novel PDE4 inhibitors derived from Chinese medicine forsythia. PLoS One 9:e115937 |
| 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 |
| 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 |
| Leikauf, George D; Pope-Varsalona, Hannah; Concel, Vincent J et al. (2012) Integrative assessment of chlorine-induced acute lung injury in mice. Am J Respir Cell Mol Biol 47:234-44 |
| Li, Hui-Hua; Li, Quan; Liu, Pengyuan et al. (2012) WNT1-inducible signaling pathway protein 1 contributes to ventilator-induced lung injury. Am J Respir Cell Mol Biol 47:528-35 |
| Bein, Kiflai; Leikauf, George D (2011) Acrolein - a pulmonary hazard. Mol Nutr Food Res 55:1342-60 |
| Lindsey, James Y; Ganguly, Koustav; Brass, David M et al. (2011) c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice. Am J Respir Crit Care Med 183:1644-52 |
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