Clinical drug development in IPF is hindered by the lack of mechanistically-relevant endpoints. The primary objective of the Longitudinal Cohort Core is to supply longitudinal clinical data and biological samples (blood and BAL) to Projects 1-3 to be used in the identification of candidate mechanistically-informative molecular markers of ER stress, TGFB activation, and EMT. Mechanistically-informative molecular markers would be extremely useful in subject selection and as endpoints in early phase studies of potential drug agents identified in Projects 1-3, allowing for more rapid and efficient assessment of biological effect. Using the blood and BAL from this core, we will show that candidate mechanistically-informative molecular markers are measurable in clinically-accessible compartments of patients with IPF. Molecular marker levels will be compared between IPF and control subjects, and correlated with baseline demographic and clinical data. The longitudinal stability of candidate mechanistically-informative molecular markers will also be assessed. It is anticipated that experiments supported by the Longitudinal Cohort Core will result in the identification of novel, mechanistically-informative molecular markers of ER stress, avp6-mediated TGFB activation, and EMT that are easily measurable in patients with IPF and are relatively stable over time.Such molecular markers will help identify appropriate subjects for future early-phase clinical trials of drug agents and could serve as mechanistically-sensitive endpoints in these trials, to be conducted during the second 5 years of this translational program project grant.

Public Health Relevance

The Longitudinal Cohort Core directly addresses an important barrier to translational research in the field of IPF: the lack of easily measurable mechanistically-informative molecular markers. This core will advance the field of translational IPF research by helping to identify mechanistically-informative molecular markers that will allow for rapid and efficient assessment of drug effect in early phase clinical trials.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01HL108794-03
Application #
8703758
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
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