Idiopathic pulmonary fibrosis (IPF) is one of the most pernicious forms of lung fibrogenesis and currently has no clearly effective treatments. Whereas the etiology of IPF remains enigmatic, there is evidence of dysregulations of several major molecular pathways in lung fibroblasts of IPF patients, including apoptosis/survival pathways as well as TGF-?, Akt, and MAPK signaling. In our preliminary studies, we found that the expression of miR-21 is upregulated in the lungs of mice with bleomycin-induced lung fibrosis and in the lungs of patients with IPF. Target predictions as well as previous studies demonstrate that miR-21 regulates the expression of PDCD4, Smad7, Spry1, and PTEN. These proteins are critical negative regulators of cell proliferation and survival as well as TGF-?, PI3K, and MAPK signaling. This information, together with our preliminary data, suggests that miR-21 may play an important role as an integrator in initiation and progression of IPF. Therefore, miR-21 appears to be a potential target for developing novel therapeutics to treat IPF. Our preliminary data showing that sequestering miR-21 by anti-miR-21 probes diminishes the severity of bleomycin induced lung fibrosis lend a strong support to this hypothesis. In this proposal, we aim to 1) characterize miR-21 expression in human lung fibroblasts, in the lungs of mice with bleomycin induced pulmonary fibrosis and in the lungs of patients with IPF;2) delineate the role of miR-21 in vivo during bleomycin induced lung fibrosis;3) delineate the mechanisms by which miR-21 regulates lung fibrosis;4) delineate the role of miR-21 in modulating the ex vivo pathological properties of lung fibroblasts from IPF patients.

Public Health Relevance

MicroRNAs are important regulators of many essential cellular and developmental events. Deregulations of microRNA expression have been shown to be involved in a number of diseases; such as cancer; cardiovascular diseases; and diabetes. However; whether microRNAs regulate lung injury and repair; processes that occur in idiopathic pulmonary fibrosis (IPF) has not been elucidated. We found that the expression of miR-21 is upregulated in mouse lungs with bleomycin induced lung fibrosis and lungs of patients with IPF and miR-21 promotes the fibrogenic activity of TGF- in human fibroblasts. The studies proposed in this application should not only improve understanding of the roles of miR-21 in the pathogenesis of lung fibrosis; but also are likely to suggest novel therapeutic interventions aimed at decreasing the severity of lung fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105473-04
Application #
8622213
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
2011-04-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$688,550
Indirect Cost
$218,550
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Cui, Huachun; Banerjee, Sami; Xie, Na et al. (2016) MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation. Am J Respir Cell Mol Biol 54:843-52
Tan, Zheng; Xie, Na; Cui, Huachun et al. (2015) Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. J Immunol 194:6082-9
Tan, Zheng; Xie, Na; Banerjee, Sami et al. (2015) The monocarboxylate transporter 4 is required for glycolytic reprogramming and inflammatory response in macrophages. J Biol Chem 290:46-55
Xie, Na; Liu, Gang (2015) ncRNA-regulated immune response and its role in inflammatory lung diseases. Am J Physiol Lung Cell Mol Physiol 309:L1076-87
Cui, Huachun; Xie, Na; Thannickal, Victor J et al. (2015) The code of non-coding RNAs in lung fibrosis. Cell Mol Life Sci 72:3507-19
Huang, Shengping; Liu, Shufeng; Fu, Jia J et al. (2015) Monocyte Chemotactic Protein-induced Protein 1 and 4 Form a Complex but Act Independently in Regulation of Interleukin-6 mRNA Degradation. J Biol Chem 290:20782-92
Xie, Na; Tan, Zheng; Banerjee, Sami et al. (2015) Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis. Am J Respir Crit Care Med 192:1462-74
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
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
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

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