Pulmonary fibrosis is responsible for morbidity and mortality in a large number of pediatric and adult lung disorders. Currently there are no approved medical treatments for fibrotic disease emphasizing the urgency of identifying novel and effective therapies. This proposal will identify signaling pathways mediating pulmonary fibroproliferation in both mouse and human fibrotic lung disease. Data from our laboratory has identified a primary role for the PiSK/mTORCI signaling pathways in mediating pulmonary fibrosis in transgenic mice over-expressing transforming growth factor-a (TGFa). The current application tests the hypothesis that pulmonary fibrosis is mediated through activation of PI3K and MAPK signaling pathways converging through the S6 ribosomal protein kinase (p70S6K) downstream of mTORCI We propose to test pharmacologic inhibitors for the above signaling pathways alone or in combination in vivo using the TGFa- driven transgenic fibrosis model to determine strategies which will both prevent the progression as well as reverse established and developing fibrotic lesions. We will administer pharmacologic inhibitors to mice that are currently in clinical oncology trials. We will also validate biomarkers of signaling pathway activation for the ERK, Akt and p70S6K pathway in idiopathic pulmonary fibrosis samples. The investigators assembled to perform the studies in this proposal are a multidisciplinary team with extensive expertise in a number of disciplines necessary to complete this proposal including cell signaling pathways, protein biochemistry and pulmonary physiology. These studies will generate preclinical data which will identify novel anti- fibroproliferative drugs and support future clinical trials in disorders causing pulmonary fibrosis.

Public Health Relevance

This proposal will identify targetable signaling pathways mediating pulmonary fibrosis. The long term goal is to produce pre-clinical data which will identify specific pharmacologic signaling pathway inhibitors currently In clinical oncology trials that can be utilized for future studies in human fibrotic lung disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL107159-02
Application #
8259727
Study Section
Special Emphasis Panel (ZHL1-CSR-D (F1))
Program Officer
Eu, Jerry Pc
Project Start
2011-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$461,677
Indirect Cost
$153,939
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Madala, Satish K; Edukulla, Ramakrishna; Phatak, Mukta et al. (2014) Dual targeting of MEK and PI3K pathways attenuates established and progressive pulmonary fibrosis. PLoS One 9:e86536
Madala, Satish K; Schmidt, Stephanie; Davidson, Cynthia et al. (2012) MEK-ERK pathway modulation ameliorates pulmonary fibrosis associated with epidermal growth factor receptor activation. Am J Respir Cell Mol Biol 46:380-8