Abstract

Anti-VEGF therapy is the current mainstay for treating wet age-related macular degeneration (AMD). The efficacy of anti-VEGF therapy is still limited, and some patients failed to respond to the treatment. No drug is currently available for subretinal fibrosis associated with AMD. Therefore, there is a great need for developing alternative or superior approaches to the current anti-VEGF therapy to combat choroidal neovascularization (CNV) and subretinal fibrosis in AMD. Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells can lead to fibrosis. However, the contribution of RPE EMT in AMD pathogenesis remains undefined. MicroRNAs belong to a large group of noncoding RNAs which can regulate diverse pathways in different cell types. The involvement of miRNAs in CNV, RPE EMT and fibrosis remains unclear. This project focuses on elucidating the function and mechanism of miRNAs in the context of complex pathological processes involved in AMD, including CNV, EMT of the RPE cells and fibrosis. The contribution of EMT of RPE cells in AMD mouse models will be examined by genetic lineage tracing. The organizing hypothesis of the proposal is that a single miRNA, miR-24, can repress CNV, EMT of RPEs and fibrosis, therefore representing an excellent ?one drug/multiple targets? model for treating AMD. In addition, the contribution of EMT of RPE cells in AMD pathogenesis will also be established.
Aim I is to define the function of miR-24 in ocular neovascularization, inflammation and fibrosis.
Aim II is to determine the role of miR-24-regulated EMT and fibrosis of RPE cells.

Public Health Relevance

Pathological angiogenesis and fibrosis underlie the pathogenesis of several ocular diseases including age-related macular degeneration (AMD). The proposed study is to elucidate the function of microRNAs in the context of complex pathological processes involved in AMD, including choroidal neovascularization (CNV), epithelial-mesenchymal transition (EMT) of the retinal pigment epithelial (RPE) cells and fibrosis. Findings from the proposed project will lead to the development of miRNA-based therapy for both CNV and fibrosis in AMD based on ?one drug/multiple targets? model.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY021862-07A1
Application #
9747585
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2011-09-01
Project End
2022-06-30
Budget Start
2019-09-01
Budget End
2020-06-30
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Tulane University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118

  Publications

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

Showing the most recent 10 out of 24 publications