Idiopathic pulmonary fibrosis (IPF) is one ofthe most pernicious forms of lung fibrogenesis and currently has no clearly effective treatments. Whereas the etiology of IPF remains enigmatic, there is a plenty of evidence showing dysregulated fibrogenesis, differentiation, contractility and migration of pulmonary fibroblasts from IPF lungs. However, the role of miRNAs in regulation of such aberrant activities in IPF fibroblasts (IPF-Fbs)is unknown. In our preliminary studies, we found that the expression of miR-31 is downregulated in the lungs of mice with bleomycin induced lung fibrosis. Target predictions demonstrate that miR-31 regulates the expression of integrin alphas and RhoA. These proteins are critical regulators of fibrogenesis, differentiation, contractility and migration of pulmonary myofibroblasts. This information, together with our preliminary data, suggests that miR-31 may play an important role in initiation and progression of IPF. Therefore, miR-31 appears to be a potential target for developing novel therapeutics to treat IPF. Our preliminary data showing that introduction of miR-31 mimics diminishes the severity of bleomycin induced lung fibrosis lend a strong support to this hypothesis. In this proposal, we aim to;determine the transcriptional and epigenetic mechanisms by which miR-31 is downregulated in IPF-Fbs;determine if miR-31 targets RhoA and integrin alphas, and thereby regulating the contractile, migratory, and fibrogenic activities of IPF-Fbs;determine if reconstitution of pulmonary miR-31 through intra-tracheal or intra-pleural delivery demonstrates therapeutic potentials in treating lung fibrosis in mouse models;determine if miR-31 inhibits PMC-myofibroblast differentiation/activation, if miR-31 expression is regulated by Src kinase signaling pathways, and if the antifibrogenic activity of miR-31 is mediated by N0X4 in IPF-Fbs.

Public Health Relevance

The studies proposed in this application should not only improve the understanding ofthe role of miR-31 in the pathogenesis of IPF, but also provide solid foundation for moving miR-31 therapeutics to clinical trials in treating this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL114470-01A1
Application #
8582303
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (M1))
Project Start
Project End
Budget Start
2013-09-16
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$371,137
Indirect Cost
$118,591
Name
University of Alabama Birmingham
Department
Type
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Huang, Wen-Tan; Akhter, Hasina; Jiang, Chunsun et al. (2015) Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis. Exp Gerontol 61:62-75
Thannickal, Victor J; Zhou, Yong; Gaggar, Amit et al. (2014) Fibrosis: ultimate and proximate causes. J Clin Invest 124:4673-7
Xie, Na; Cui, Huachun; Banerjee, Sami et al. (2014) miR-27a regulates inflammatory response of macrophages by targeting IL-10. J Immunol 193:327-34
Desai, Leena P; Zhou, Yong; Estrada, Aida V et al. (2014) Negative regulation of NADPH oxidase 4 by hydrogen peroxide-inducible clone 5 (Hic-5) protein. J Biol Chem 289:18270-8
Blackwell, Timothy S; Tager, Andrew M; Borok, Zea et al. (2014) Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. Am J Respir Crit Care Med 189:214-22
Hu, Meng; Che, Pulin; Han, Xiaosi et al. (2014) Therapeutic targeting of SRC kinase in myofibroblast differentiation and pulmonary fibrosis. J Pharmacol Exp Ther 351:87-95
Bai, Guangxing; Hock, Thomas D; Logsdon, Naomi et al. (2014) A far-upstream AP-1/Smad binding box regulates human NOX4 promoter activation by transforming growth factor-?. Gene 540:62-7
Hecker, Louise; Logsdon, Naomi J; Kurundkar, Deepali et al. (2014) Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med 6:231ra47
Cui, Huachun; Xie, Na; Tan, Zheng et al. (2014) The human long noncoding RNA lnc-IL7R regulates the inflammatory response. Eur J Immunol 44:2085-95
Karki, Suman; Surolia, Ranu; Hock, Thomas David et al. (2014) Wilms' tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis. FASEB J 28:1122-31

Showing the most recent 10 out of 13 publications