Fibroproliferative disorders are common, progressive and refractory to available therapy. Fibroblasts derived from fibroproliferative lesions manifest an unexplained autonomy for growth and survival signals. In this revised proposal, we propose to study lung fibroblasts from patients with Idiopathic Pulmonary Fibrosis (IPF), a prototype fibroproliferative disease, and elucidate the mechanism of autonomous function using our recent discoveries in cancer biology as a guide. In studies of human breast carcinoma, we discovered that autonomy is conferred by deregulation of the cap-dependent translation initiation machinery, designated eIF4F. In normal cells, eIF4F receives signals from matrix and growth factor receptors and their downstream intermediates, and orchestrates these inputs into a physiological growth response. In cancer cells, eIF4F serves to integrate and amplify diverse growth and survival signals emanating from a plethora of growth-related genes to confer autonomy. Here we show preliminary data indicating that aberrant activation of eIF4F is a property of IPF fibroblasts;that activating eIF4F in fibroblasts stimulates cell cycle entry in the absence of growth factors;and that mice genetically engineered to lack negative regulators of eIF4F have an exaggerated fibrotic response. We therefore hypothesize that deregulated translational control of transcripts governing cell cycle transit lies on the causal pathway to fibrosis;and propose 2 specific aims to test this hypothesis:
Specific Aim 1 : Classify transcripts in IPF fibroblasts that display coordinate changes in translational efficiency into discrete groups based on shared chemical and biological characteristics. A. Chemical: Nucleotide sequences that comprise known or candidate RNA regulatory elements. B. Biological: Assigned function.
Specific Aim 2 : Focusing on transcripts encoding cell cycle regulators, determine whether disrupting regulatory element function attenuates IPF fibroblast proliferative autonomy. A. Known regulatory elements. B. Newly discovered regulatory elements. If successful, our studies will precisely identify derangements in the translational step of gene expression that confer IPF fibroblasts with proliferative autonomy, thus revealing new classes of molecular targets for antifibrotic therapy in the lung and other organs.

Public Health Relevance

. Many human diseases are characterized by scar tissue accumulation that leads to organ dysfunction and death. Scarring, also called fibrosis, can affect many different organs including the lung, liver, kidney, heart, vasculature and skin;and is often very difficult to treat. Here we propose to study the cell producing scar tissue, the fibroblast, in a deadly form of lung scarring that afflicts more than 35,000 people in the US, termed idiopathic pulmonary fibrosis (IPF). Our pilot experiments point to abnormal activation of the cellular machinery that produces protein, in a pattern similar to that seen in cancer. Our goal in this study is to understand how the biology of fibroblasts can be redirected by abnormalities in the protein synthesis machinery in a manner that leads to lung fibrosis. This information has the potential to lead to new treatments for all scarring diseases by revealing new molecular targets for antifibrotic therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089249-04
Application #
8119476
Study Section
Special Emphasis Panel (ZRG1-RES-B (02))
Program Officer
Eu, Jerry Pc
Project Start
2008-09-19
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$419,662
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
Wang, Huan; Hou, Lei; Kwak, Dongmin et al. (2016) Increasing Regulatory T Cells With Interleukin-2 and Interleukin-2 Antibody Complexes Attenuates Lung Inflammation and Heart Failure Progression. Hypertension 68:114-22
Wang, Huan; Kwak, Dongmin; Fassett, John et al. (2016) CD28/B7 Deficiency Attenuates Systolic Overload-Induced Congestive Heart Failure, Myocardial and Pulmonary Inflammation, and Activated T Cell Accumulation in the Heart and Lungs. Hypertension 68:688-96
Liu, Xiaoyu; Hou, Lei; Xu, Dachun et al. (2016) Effect of asymmetric dimethylarginine (ADMA) on heart failure development. Nitric Oxide 54:73-81
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
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
Liu, Xiaoyu; Kwak, Dongmin; Lu, Zhongbing et al. (2014) Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling. Hypertension 64:738-44
Wang, Huan; Xu, Xin; Fassett, John et al. (2014) Double-stranded RNA-dependent protein kinase deficiency protects the heart from systolic overload-induced congestive heart failure. Circulation 129:1397-406
Xu, Xin; Lu, Zhongbing; Fassett, John et al. (2014) Metformin protects against systolic overload-induced heart failure independent of AMP-activated protein kinase ?2. Hypertension 63:723-8
Bache, Robert J; Chen, Yingjie (2014) NOX2-induced myocardial fibrosis and diastolic dysfunction: role of the endothelium. J Am Coll Cardiol 63:2742-4

Showing the most recent 10 out of 13 publications