This translational program project grant is designed to develop new effective therapies for idiopathic pulmonary fibrosis (IPF). The grant is entirely focused on developing new drugs that specifically target known pathways in alveolar epithelial cells that are critical fo the development of pulmonary fibrosis. The grant will also use a novel, mechanism-based approach to identify informative biomarkers from human cells and tissues that should provide early indicators of the effectiveness of each of the drugs we develop in subsequent early phase clinical trials in patients with IPF. The rationale for this grant is that IPF is a consequence of n-going epithelial stress and apoptosis, which leads to activation of extracellular latent TGFbeta by the alpha nu beta integrin on alveolar epithelial cells, which in turn induces progressive fibrosis at least in part through induction of TGFbeta signaling in epithelial cells. The proposal includes 3 projects which will each utilize multiple mouse models of pulmonary fibrosis to evaluate the efficacy of existing drug agents that target apoptosis induced by the unfolded protein response, integrin-mediated TGFbeta activation and TGFbeta signaling in epithelial cells, and to develop novel agents with improved potency and reduced systemic toxicity. By parallel analysis of the effects of these drug agents on human alveolar epithelail cells and human lung fragments, these projects will further asess the applicability of murine findings to humans. Each project will also take advantage of serial samples of blood and BAL cells and fluid from patients with IPF and healthy controls to characterize the utiltiy and reproducibility of putative biologically informative biomarkers. These projects will be supported by a human lung cell and tissue core, a longitudinal cohort core, a mediciinal chemistry core and a centralized administrative core. By performing extenisve pre-clinical analysis of the most promising candidate drugs, establishing their effectiveness in human lung, and developing read-outs of drug effectiveness that can be detected in blood, bronchoalveolar lavage fluid or alveolar macrophages, the work performed should lay the groundwork for clinical trials of the most promising candidates in a planned second phase of this program.

Public Health Relevance

This grant will address two critical needs - developing effective treatments for pulmonary fibrosis and better ways to determine if drugs are actually hitting their targets. By targeting specific well-defined pathways, modifying drugs for delivery into the airways, and identifying markers of drug efficacy from readilly available sites, we hope to dramatically improve current approaches to treatment of pulmonary fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108794-02
Application #
8527831
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (M1))
Program Officer
Eu, Jerry Pc
Project Start
2012-08-09
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$2,431,465
Indirect Cost
$877,341
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Stuart, Bridget D; Lee, Joyce S; Kozlitina, Julia et al. (2014) Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir Med 2:557-65
Travis, Mark A; Sheppard, Dean (2014) TGF-* activation and function in immunity. Annu Rev Immunol 32:51-82
Wolters, Paul J; Collard, Harold R; Jones, Kirk D (2014) Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol 9:157-79
Ghosh, Rajarshi; Wang, Likun; Wang, Eric S et al. (2014) Allosteric inhibition of the IRE1? RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158:534-48
Xi, Ying; Tan, Kevin; Brumwell, Alexis N et al. (2014) Inhibition of epithelial-to-mesenchymal transition and pulmonary fibrosis by methacycline. Am J Respir Cell Mol Biol 50:51-60
Sheppard, Dean (2013) ROCKing pulmonary fibrosis. J Clin Invest 123:1005-6
Friedman, Scott L; Sheppard, Dean; Duffield, Jeremy S et al. (2013) Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 5:167sr1