This project focuses on microRNA mechanisms on ocular angiogenesis. Angiogenesis plays a central role in eye development and also many major blinding retinal diseases, such as age related macular degeneration (AMD).The discovery of MicroRNAs as small endogenous RNAs regulating gene expression post-transcriptionally has revolutionized our understanding of genetic pathway networks, and ignited tremendous studies to explore microRNA therapeutics for numerous diseases. Our broad long-term goals are: (a) to understand the mechanisms of how specific microRNAs regulate ocular vascular development and (b) to decipher the roles of these microRNAs in vascular retinopathies. Our recent studies show that a specific microRNA, miR-126, is an endothelial cell specific microRNA regulating angiogenic pathways in response to vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). We also have preliminary data that miR-126 is expressed specifically in the endothelium in the retina/choroid, and is required for sprouting retinal angiogenesis. Our organizing hypothesis for this proposal is that by regulating multiple angiogenic pathways miR-126 plays a critical regulatory role in ocular angiogenesis and in the pathogenesis of neovascular AMD. As a small molecule with multiple regulatory functions, miR-126 would be an attractive therapeutic target for blinding vascular retinopathies.
Specific Aim I is to define the expression pattern and regulation mechanism of miR-126 in the retina/choroid.
Specific Aim II is to identify the requirement and mechanism whereby miR-126 regulates retinal vascular development.
Specific Aim III is to determine the mechanism by which miR-126 regulates neovascularization in a laser induced choroidal neovascularization model.

Public Health Relevance

Angiogenesis plays a central role in retinal vascular development and also many major blinding retinal diseases. The current study is targeted to uncover the mechanism whereby microRNAs regulate retinal vascular development and neovascular AMD using genetic mouse models and LNA-anti-miR technologies, which may paves the road for future microRNA therapeutics in vascular retinopathies.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021862-05
Application #
8725162
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Shen, Grace L
Project Start
2011-09-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Tulane University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Hao, Yi; Zhou, Qinbo; Ma, Jing et al. (2016) miR-146a is upregulated during retinal pigment epithelium (RPE)/choroid aging in mice and represses IL-6 and VEGF-A expression in RPE cells. J Clin Exp Ophthalmol 7:
Zhou, Qinbo; Anderson, Chastain; Hanus, Jakub et al. (2016) Strand and Cell Type-specific Function of microRNA-126 in Angiogenesis. Mol Ther 24:1823-1835
Hanus, Jakub; Zhao, Fangkun; Wang, Shusheng (2016) Current therapeutic developments in atrophic age-related macular degeneration. Br J Ophthalmol 100:122-7
Li, Ming; Cheng, Hongbo; Guo, Ping et al. (2016) Iris ultrastructure in patients with synechiae as revealed by in vivo laser scanning confocal microscopy : In vivo iris ultrastructure in patients with Synechiae by Laser Scanning Confocal Microscopy. BMC Ophthalmol 15 Suppl 1:46
Hanus, J; Anderson, C; Sarraf, D et al. (2016) Retinal pigment epithelial cell necroptosis in response to sodium iodate. Cell Death Discov 2:16054
Hanus, Jakub; Kolkin, Alexander; Chimienti, Julia et al. (2015) 4-Acetoxyphenol Prevents RPE Oxidative Stress-Induced Necrosis by Functioning as an NRF2 Stabilizer. Invest Ophthalmol Vis Sci 56:5048-59
Hanus, Jakub; Zhang, Hongmei; Chen, David H et al. (2015) Gossypol Acetic Acid Prevents Oxidative Stress-Induced Retinal Pigment Epithelial Necrosis by Regulating the FoxO3/Sestrin2 Pathway. Mol Cell Biol 35:1952-63
Hanus, Jakub; Anderson, Chastain; Wang, Shusheng (2015) RPE necroptosis in response to oxidative stress and in AMD. Ageing Res Rev 24:286-98
Schober, Andreas; Nazari-Jahantigh, Maliheh; Wei, Yuanyuan et al. (2014) MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med 20:368-76
Zhou, Qinbo; Anderson, Chastain; Zhang, Hongmei et al. (2014) Repression of choroidal neovascularization through actin cytoskeleton pathways by microRNA-24. Mol Ther 22:378-89

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