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-a (TGFa) and TGFp. These growth factors, in turn, control proliferation and the transcription of genes involved in differentiated function. Previously, a genetic locus that harbors TGFa was linked to, and TGFa 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 TGFa transgenic mice have been generate to permit detailed investigations of the temporal role of this growth factor in lung injury. Recently, we found TGFp is released, and many TGFp responsive transcripts are altered in our model of acute lung injury. Our central hypothesis is that the interplay between TGFa and TGFp 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 TGFa and TGFp in acute lung injury, we propose to manipulate TGFa signaling and monitor the consequences on TGFp signaling.
The Specific Aims of this proposal seek to: 1) Identify the molecular mechanisms responsible for TGFa/EGFR mediated protection in acute lung injury, 2) Evaluate the therapeutic efficacy of TGFa induction and TGFa/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 TGFa and TGFp 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 TGFa/EGFR signaling and the possible interactions of TGFa with TGFp in acute lung injury. At the completion of this project, we expect to: 1) Identify the transcriptional events modulated by TGFa that leads to protection from acute lung injury, 2) Gain a better understanding of how TGFp functions in acute lung injury, and 3) Determine whether pulmonary fibrosis is an untoward consequence of activating TGFa/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 TGFa/EGFR signaling could be considered for the treatment of acute lung injury. PERFORMAMCE SITE(S,) (organization, city, state) University of Cincinnati, Cincinnati, Ohio KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Role on Project George D. Leikauf, Ph.D. University of Cincinnati P.I. Thomas Korfhagen, M.D., Ph.D. Children's Hospital Medical Ctr. Co-ln. William Hardie, M.D. Children's Hospital Medical Ctr. Co-ln. Disclosure Permission Statement. Applicable to SBIR/STTR Only. Seeinstructions D Yes D No PHS398 (Rev.05/01) Page 2 Principal Investigator/Program Director (Last, First, Middle): Leikauf, George D. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,
| 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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