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.

Public Health Relevance

This PPG will provide mechanistic insight into the molecular processes that make an IPF fibroblast abnormal by uncovering those components of the myofibroblast cellular machinery that result in unrelenting fibrosis in IPF. We believe the work proposed within this PPG represents some of the best science in IPF research and will advance the field and lead to novel therapeutic strategies to limit the progressive fibrosis of IPF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL091775-04
Application #
8242760
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Eu, Jerry Pc
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$1,673,077
Indirect Cost
$399,441
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
Liu, Tianju; Yu, Hongfeng; Ullenbruch, Matthew et al. (2014) The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis. PLoS One 9:e88362
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
Parker, Matthew W; Rossi, Daniel; Peterson, Mark et al. (2014) Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J Clin Invest 124:1622-35
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
Liu, Tianju; Ullenbruch, Matthew; Young Choi, Yoon et al. (2013) Telomerase and telomere length in pulmonary fibrosis. Am J Respir Cell Mol Biol 49:260-8
Nho, Richard Seonghun; Peterson, Mark; Hergert, Polla et al. (2013) FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas. PLoS One 8:e61017
Nakashima, Taku; Liu, Tianju; Yu, Hongfeng et al. (2013) Lung bone marrow-derived hematopoietic progenitor cells enhance pulmonary fibrosis. Am J Respir Crit Care Med 188:976-84
Hu, Biao; Wu, Zhe; Hergert, Polla et al. (2013) Regulation of myofibroblast differentiation by poly(ADP-ribose) polymerase 1. Am J Pathol 182:71-83
Hu, Biao; Phan, Sem H (2013) Myofibroblasts. Curr Opin Rheumatol 25:71-7
Hu, Biao; Wu, Zhe; Nakashima, Taku et al. (2012) Mesenchymal-specific deletion of C/EBPýý suppresses pulmonary fibrosis. Am J Pathol 180:2257-67

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