Idiopathic pulmonary fibrosis (IPF) accounts for more than half of the cases of interstitial lung disease. Patients suffering from IPF develop a progressive loss of lung function and die, on average, 3 years after diagnosis. Alveolar type 11 cells are abormal in IPF lungs. However, their precise role in disease pathogenesis remains undefined. This program project grant examines the novel hypothesis that epithelial cells directly participate in the formation of lung fibrosis via three pathologic processes: ER stress, activation of TGPB by the epithelial integrin avB6, and epithelial to mesenchymal transition. Considering this hypothesis, the primary objective of this translational program project grant centers on developing novel drugs that target these pathological processes in IPF alveolar type 11 cells. In support of the overall objectives of the program project grant. The Human tissue core will: 1. provide a centralized resource for processing, cataloging and storing human biological samples obtained from patients with IPF and normal controls, 2. obtain highly purified isolates of alveolar type II cells from normal and fibrotic human lungs for use in testing candidate drug compounds, and 3;provide a centralized resource forthe comparative analysis of protein and gene expression in human type II cells, lung fragments and slices isolated from normal and IPF lungs. The core will perform expression microarrays and miRNA arrays on cells and tissues induced to undergo ER stress, avB6-mediated TGFB activation or EMT in the presence or absence of drugs to inhibit these pathways, to identify mechanistically informative biomarkers that can be characterized by each project. The cells and tissues from this centralized resource will be used to refine candidate drugs targeting each of the three epithelial cell dependent profibrotic pathways. Project 1 to examine compounds manipulating the unfolded protein response both in IPF type 11 cells, which exhibit an increased UPR, and in normal type 11 cells whose UPR is activated by culture in tunicamycin. Fragments of lung tissue will be used in project 2 to test compounds inhibiting epithelial cell dependent TGFB activation by the integrin avB6. For project 3, the leader of the human tissue core developed novel methods using FACS sorting to isolate highly pure populations of alveolar type II cells from normal and fibrotic human lungs. These cells will be used in a novel in vitro model of EMT to test candidate compounds blocking TGPB signalling and EMT.

Public Health Relevance

By completing the proposed aims the human tissue core will provide quality human samples that can be used for studies that address significant gaps in knowledge of the pathogenesis of IPF and aid in the development of novel therapies targeting pathologic processes including: 1) the unfolded protein response. 2) epithelial cell dependent TGFB activation and 3) epithelial to mesenchymal transition.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1-CSR-Q (M1))
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University of California San Francisco
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