MicroRNAs, a class of 21-22 nucleotide non-coding small RNAs, are important regulators of gene expression and have been shown to modulate a broad range of cellular and developmental events. We have found that the expression of miR147 is upregulated in LPS stimulated cells and miR147 has anti-inflammatory properties which diminish activation in macrophages. Our data therefore suggest that specific microRNAs participate in regulating acute TLR4 induced inflammatory events and that modulation of microRNAs may have potential therapeutic benefit in life-threatening inflammatory conditions, such as ALI. Our hypothesis is that miR147 participates in the regulation of acute inflammatory responses and play a major role in determining the development, perpetuation, and severity of ALI.
Our specific aims are: 1) To characterize the role of miR147 in regulating TLR4 induced inflammatory responses by delineating the mechanisms leading to LPS induced upregulation in the expression of miR147, elucidating the role that miR147 occupies in modulating LPS induced cellular activation, and delineating the mechanisms through which miR147 affects LPS induced cellular activation. 2) To explore if modulation of the expression of miR147 attenuates LPS induced ALI by determining the expression of miR147 in the lungs of LPS treated mice and exploring if modulation of miR147 expression can attenuate LPS induced ALI. The proposed studies should not only improve understanding of cellular mechanisms leading to ALI, but also are likely to suggest novel therapeutic interventions aimed at decreasing the incidence and/or severity of ALI.

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 acute inflammatory responses and acute inflammation related diseases, including acute lung injury (ALI) has not been elucidated. We found that the expression of miR147 is upregulated in LPS stimulated macrophages and mouse lungs and miR147 has anti-inflammatory activities. The studies proposed in this application should not only improve understanding of the roles of microRNAs in regulation of LPS induced inflammatory responses and acute lung injury, but also are likely to suggest novel therapeutic interventions aimed at decreasing the incidence and/or severity of acute lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL097218-01A1
Application #
7990182
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2010-06-01
Project End
2012-04-30
Budget Start
2010-06-01
Budget End
2011-04-30
Support Year
1
Fiscal Year
2010
Total Cost
$183,125
Indirect Cost
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
Banerjee, Sami; Xie, Na; Cui, Huachun et al. (2013) MicroRNA let-7c regulates macrophage polarization. J Immunol 190:6542-9
Huang, Shengping; Miao, Ruidong; Zhou, Zhou et al. (2013) MCPIP1 negatively regulates toll-like receptor 4 signaling and protects mice from LPS-induced septic shock. Cell Signal 25:1228-34
Liu, Gang; Abraham, Edward (2013) MicroRNAs in immune response and macrophage polarization. Arterioscler Thromb Vasc Biol 33:170-7
Yang, Shanzhong; Cui, Huachun; Xie, Na et al. (2013) miR-145 regulates myofibroblast differentiation and lung fibrosis. FASEB J 27:2382-91
Miao, Ruidong; Huang, Shengping; Zhou, Zhou et al. (2013) Targeted disruption of MCPIP1/Zc3h12a results in fatal inflammatory disease. Immunol Cell Biol 91:368-76
Yang, Shanzhong; Banerjee, Sami; Freitas, Andressa de et al. (2012) miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 302:L521-9
Yang, Shanzhong; Xie, Na; Cui, Huachun et al. (2012) miR-31 is a negative regulator of fibrogenesis and pulmonary fibrosis. FASEB J 26:3790-9
de Freitas, Andressa; Banerjee, Sami; Xie, Na et al. (2012) Identification of TLT2 as an engulfment receptor for apoptotic cells. J Immunol 188:6381-8
Lazrak, Ahmed; Chen, Lan; Jurkuvenaite, Asta et al. (2012) Regulation of alveolar epithelial Na+ channels by ERK1/2 in chlorine-breathing mice. Am J Respir Cell Mol Biol 46:342-54
Yang, Shanzhong; Banerjee, Sami; de Freitas, Andressa et al. (2012) Participation of miR-200 in pulmonary fibrosis. Am J Pathol 180:484-93

Showing the most recent 10 out of 14 publications