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Toshihide Kurihara, Peter Westenskow, Stephen Bravo, Mollie Friedlander, Edith Aguilar, Martin Friedlander; Pathological Role of RPE-derived microRNA Cluster miR17-92 in Subretinal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2013;54(15):366.
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© ARVO (1962-2015); The Authors (2016-present)
MicroRNAs (miRNAs) are endogenous short noncoding RNAs that regulate mRNA expression posttranscriptionally. Mounting evidence indicates that these molecules have important physiological and pathological functions. However, little is known about their roles in pathological subretinal neovascularization, a condition that is characteristic of several retinal diseases including age-related macular degeneration and Juxtafoveal Macular Telangiectasia. In this study, we analyzed miRNA expression in two different animal models and characterized their functions using targeted/conditional gene deletion technology.
miRNA expression was profiled in retinal pigment epithelium (RPE)/choroid complex from very low density lipoprotein receptor knockout mice (VLDLR-/-) and wild type mice of laser-induced choroidal neovascularization model (laser-CNV). Inducible RPE-specific Cre transgenic mice were crossed with miRNA cluster floxed mice to obtain RPE-specific miRNA cluster knockout mice. These mice were further crossed with VLDLR mutants. The formation of outer retinal neovascularization in VLDLR mutants and laser-CNV with or without the miRNA cluster deletion in RPE was examined by whole mount staining. Morphological and functional analyses were performed with electron microscopy and full-field electroretinography.
Six individual miRNAs from miRNA cluster miR17-92 were significantly upregulated in VLDLR-/- or laser-irradiated RPE/choroid. The RPE-specific deletion of miR17-92 did not result in adverse morphological and functional phenotypes physiologically. In contrast, outer retinal neovascular formations in VLDLR-/- and laser-CNV were significantly suppressed by miR17-92 deletion in RPE. The conditional deletion of miR17-92 significantly rescued photopic dysfunction in VLDLR-/-.
miRNAs of the miRNA cluster miR17-92 were significantly upregulated in two different animal models of neovascularization. The pathological role of miR17-92 in these models was confirmed by RPE-specific conditional gene deletion. These findings may lead to new therapeutic strategies targeting miRNAs for treatment of neovascular retinal diseases.
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