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 #
5P01HL114470-02
Application #
8735179
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Bernard, Karen; Logsdon, Naomi J; Miguel, Veronica et al. (2017) NADPH Oxidase 4 (Nox4) Suppresses Mitochondrial Biogenesis and Bioenergetics in Lung Fibroblasts via a Nuclear Factor Erythroid-derived 2-like 2 (Nrf2)-dependent Pathway. J Biol Chem 292:3029-3038
Li, Fu Jun; Surolia, Ranu; Li, Huashi et al. (2017) Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis. J Immunol 199:1596-1605
Ge, Jing; Cui, Huachun; Xie, Na et al. (2017) Glutaminolysis Promotes Collagen Translation and Stability via ?-ketoglutarate Mediated mTOR Activation and Proline Hydroxylation. Am J Respir Cell Mol Biol :
Cui, Huachun; Ge, Jing; Xie, Na et al. (2017) miR-34a promotes fibrosis in aged lungs by inducing alveolarepithelial dysfunctions. Am J Physiol Lung Cell Mol Physiol 312:L415-L424
Hough, K P; Chanda, D; Duncan, S R et al. (2017) Exosomes in immunoregulation of chronic lung diseases. Allergy 72:534-544
Sanders, Yan Y; Liu, Hui; Scruggs, Anne M et al. (2017) Epigenetic Regulation of Caveolin-1 Gene Expression in Lung Fibroblasts. Am J Respir Cell Mol Biol 56:50-61
Cui, Huachun; Ge, Jing; Xie, Na et al. (2017) miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence. Am J Respir Cell Mol Biol 56:168-178
de Andrade, Joao A; Luckhardt, Tracy (2017) What Is in a Pattern? That Which We Call Idiopathic Pulmonary Fibrosis by Any Other Pattern Would Behave Alike! Am J Respir Crit Care Med 195:10-12
Xie, Na; Cui, Huachun; Ge, Jing et al. (2017) Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis. Am J Physiol Lung Cell Mol Physiol 313:L834-L844
Surolia, Ranu; Li, Fu Jun; Wang, Zheng et al. (2017) 3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs. JCI Insight 2:e91377

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