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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Shen, Grace L
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Tulane University
Anatomy/Cell Biology
Schools of Arts and Sciences
New Orleans
United States
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Zhao, Fangkun; Anderson, Chastain; Karnes, Sara et al. (2018) Expression, regulation and function of miR-126 in the mouse choroid vasculature. Exp Eye Res 170:169-176
Yu, Bo; Wang, Shusheng (2018) Angio-LncRs: LncRNAs that regulate angiogenesis and vascular disease. Theranostics 8:3654-3675
Zhou, Qinbo; Frost, Robert J A; Anderson, Chastain et al. (2017) Let-7 contributes to diabetic retinopathy but represses pathological ocular angiogenesis. Mol Cell Biol :
Li, Xinyu; Zhao, Fangkun; Xin, Mei et al. (2017) Regulation of intraocular pressure by microRNA cluster miR-143/145. Sci Rep 7:915
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
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, 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; Zhao, Fangkun; Wang, Shusheng (2016) Current therapeutic developments in atrophic age-related macular degeneration. Br J Ophthalmol 100:122-7
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

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