Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease refractory to pharmacological therapy. It afflicts 1/10,000 individuals leading to death within 3-5 years of diagnosis unless treated by lung transplantation. In attempt to arrest this lethal disease, this Program Project focuses on the fibroproliferative process and its key cellular constituent- the myofibroblast. Despite studies indicating that IPF fibroblasts display a distinct pathological phenotype, large gaps in knowledge remain regarding differences between the pathological nature of IPF myofibroblasts responsible for progressive fibrosis and the physiological function of myofibroblasts essential for normal tissue repair. Considering this, the individual projects comprising this PPG promote a unified theme: provide direct mechanistic insight into the molecular processes that make an IPF fibroblast abnormal by uncovering components of the myofibroblast cellular machinery that result in unrelenting fibrosis in IPF, and in proper tissue healing under normal circumstances. It is our theory that a malicious alliance of cytokines and matrix macromolecules modulates the fibroblast phenotype resulting in stable pathological changes in the basic fibroblast cellular machinery that can be discerned at the level of transcription, translation and signal transduction. Within this framework, Project 1 (Henke) examines the role of integrin-matrix in regulating IPF fibroblast proliferation;Project 2 (Bitterman) investigates translational control of the fibroblast phenotype in IPF;and Project 3 (Phan) assesses transcriptional control of myofibroblast differentiation. The scientific sections are supported by an Administrative Core (Henke) and a Biospecimen and Histopathology Core (Ingbar). The Biospecimen Core functions to provide standardized tissue specimens and cell lines to be used by each investigator in order to reduce uncontrolled alterations in fibroblast phenotype possible during cell isolation and cultivation. Thus, this Program Project has gathered a group of scientists with diverse areas of expertise to work together on a common theme. A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL091775-01A1
Application #
7630815
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Reynolds, Herbert Y
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
1
Fiscal Year
2009
Total Cost
$1,710,607
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Herrera, Jeremy; Beisang, Daniel J; Peterson, Mark et al. (2018) Dicer1 Deficiency in the Idiopathic Pulmonary Fibrosis Fibroblastic Focus Promotes Fibrosis by Suppressing MicroRNA Biogenesis. Am J Respir Crit Care Med 198:486-496
Huang, Chaoqun; Xiao, Xiao; Yang, Ye et al. (2017) MicroRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation. J Biol Chem 292:16420-16439
Liu, Tianju; Yu, Hongfeng; Ding, Lin et al. (2015) Conditional Knockout of Telomerase Reverse Transcriptase in Mesenchymal Cells Impairs Mouse Pulmonary Fibrosis. PLoS One 10:e0142547
Hu, Biao; Liu, Jianhua; Wu, Zhe et al. (2015) Reemergence of hedgehog mediates epithelial-mesenchymal crosstalk in pulmonary fibrosis. Am J Respir Cell Mol Biol 52:418-28
Hu, Biao; Wu, Zhe; Bai, David et al. (2015) Mesenchymal deficiency of Notch1 attenuates bleomycin-induced pulmonary fibrosis. Am J Pathol 185:3066-75
Martins, Vanessa; Gonzalez De Los Santos, Francina; Wu, Zhe et al. (2015) FIZZ1-induced myofibroblast transdifferentiation from adipocytes and its potential role in dermal fibrosis and lipoatrophy. Am J Pathol 185:2768-76
Smith, K A; Zhou, B; Avdulov, S et al. (2015) Transforming Growth Factor-?1 Induced Epithelial Mesenchymal Transition is blocked by a chemical antagonist of translation factor eIF4E. Sci Rep 5:18233
Khalil, Wajahat; Xia, Hong; Bodempudi, Vidya et al. (2015) Pathologic Regulation of Collagen I by an Aberrant Protein Phosphatase 2A/Histone Deacetylase C4/MicroRNA-29 Signal Axis in Idiopathic Pulmonary Fibrosis Fibroblasts. Am J Respir Cell Mol Biol 53:391-9
Xia, Hong; Bodempudi, Vidya; Benyumov, Alexey et al. (2014) Identification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis. Am J Pathol 184:1369-83
Bodempudi, Vidya; Hergert, Polla; Smith, Karen et al. (2014) miR-210 promotes IPF fibroblast proliferation in response to hypoxia. Am J Physiol Lung Cell Mol Physiol 307:L283-94

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