MicroRNAs (miRNAs) are a new class of non-coding small RNAs that negatively regulate gene expression by either degrading mRNA or inhibiting protein translation. miRNAs have been shown to play very important roles in a variety of diseases, such as cancers, viral infection, genetic disorders, and cardiovascular diseases. Recently we found that miR-21, an oncogenic miRNA gene was aberrantly overexpressed in a variety of cancers, was also upregulated in the mouse cardiac hypertrophy model and rat carotid artery balloon injury model. Knockdown of miR-21 induced apoptosis in vascular smooth muscle cells and in the rat carotid artery balloon-injured model by targeting the 3'untranslated region (UTR) of the phosphatase and tensin homolog (PTEN) gene and indirectly regulated Bcl-2 gene expression in vascular smooth muscle cells (VSMCs). To further understand the molecular mechanism by which miR-21 regulates gene expression on the important signaling pathways, which play pivotal roles in vascular diseases, we constructed a lentiviral vector in which the miR-21 gene was driven by the rat smooth muscle cell specific promoter (rSM22) and generated a transgenic rat model in which miR-21 is overexpressed in VSMCs. We found that several transgenic rat founders display consistent phenotypes: growth retardation and slightly paralyzed hind limbs. This transgenic rat model will certainly provide insight to understanding miRNA functions in cardiovascular diseases and will help us further evaluate potential applications of miRNA in diagnosing and test miRNA based therapy for cardiovascular diseases.

Public Health Relevance

This proposal is to characterize transgenic rats expressing miR-21 using lentiviral vector to address the biological functions of miRNAs by targeting miR-21 gene into vascular smooth muscle cells. The phenotype and molecular mechanisms underlying the phenotypes will also be examined using this transgenic rat models by investigating how miR-21 is involved in the posttranscriptional regulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL095957-02
Application #
8019072
Study Section
Special Emphasis Panel (ZRG1-CVS-Q (90))
Program Officer
Thrasher, Terry N
Project Start
2010-01-12
Project End
2013-11-30
Budget Start
2010-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2011
Total Cost
$188,275
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Wang, Yinan; Yang, Chuanhe; Gu, Qingqing et al. (2015) KLF4 Promotes Angiogenesis by Activating VEGF Signaling in Human Retinal Microvascular Endothelial Cells. PLoS One 10:e0130341
Guo, Yuqi; Tian, Peng; Yang, Chuanhe et al. (2015) Silencing the double-stranded RNA binding protein DGCR8 inhibits ovarian cancer cell proliferation, migration, and invasion. Pharm Res 32:769-78
Chen, Zixuan; Wang, Yinan; Liu, Wen et al. (2014) Doxycycline inducible Krüppel-like factor 4 lentiviral vector mediates mesenchymal to epithelial transition in ovarian cancer cells. PLoS One 9:e105331
Guo, Yuqi; Tian, Peng; Yang, Chuanhe et al. (2013) Silencing the Double-Stranded RNA Binding Protein DGCR8 Inhibits Ovarian Cancer Cell Proliferation, Migration, and Invasion. Pharm Res :
Fan, Pei; Chen, Zixuan; Tian, Peng et al. (2013) miRNA biogenesis enzyme Drosha is required for vascular smooth muscle cell survival. PLoS One 8:e60888
Chen, Zixuan; Wu, Jianmin; Yang, Chuanhe et al. (2012) DiGeorge syndrome critical region 8 (DGCR8) protein-mediated microRNA biogenesis is essential for vascular smooth muscle cell development in mice. J Biol Chem 287:19018-28
Yue, Junming (2011) miRNA and vascular cell movement. Adv Drug Deliv Rev 63:616-22
Yang, Chuan He; Yue, Junming; Pfeffer, Susan R et al. (2011) MicroRNA miR-21 regulates the metastatic behavior of B16 melanoma cells. J Biol Chem 286:39172-8
Pan, Yaoqian; Balazs, Louisa; Tigyi, Gabor et al. (2011) Conditional deletion of Dicer in vascular smooth muscle cells leads to the developmental delay and embryonic mortality. Biochem Biophys Res Commun 408:369-74
Yue, Junming; Sheng, Yi; Ren, Aixia et al. (2010) A miR-21 hairpin structure-based gene knockdown vector. Biochem Biophys Res Commun 394:667-72

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