Abstract

This proposal will study the role of retinal pigment epithelium (RPE) in the pathogenesis of subretinal neovascularization (SRN), a key process in the exudative form of age-related macular degeneration (ARMD). Two hypotheses will be tested: (1) choroidal endothelial cell (CEC) angiogenesis, which leads to subretinal neovascularization, is modulated by factors expressed by RPE cells and that act on CECs; (2) RPE expression of angiogenesis- modulating factors is influenced by cytokines [tumor necrosis factor- alpha (TNF-alpha), transforming growth factors (TGF-beta)] that are released by activated macrophages. To test these hypotheses, the applicants will test the effects of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor (PAI) and tissue inhibitor of metalloproteinase (TIMP) on human tube-forming CECs in an in vitro angiogenesis model (CECs are grown in a collagen gel where they form a network of tube-like structures that have lumens). The CECs will also be exposed to an overlay of cytokine-activated APE cells or RPE cells genetically-transduced to express angiogenic or antiangiogenic factors. Effects of the designated factors will also be tested in vivo using rabbit and primate models of SAN, by subretinal transplantation of the genetically transduced RPE cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY001545-24
Application #
6150752
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Dudley, Peter A
Project Start
1983-02-01
Project End
2001-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
24
Fiscal Year
2000
Total Cost
$303,082
Indirect Cost

  Institution

Name
University of Southern California
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Kerur, Nagaraj; Fukuda, Shinichi; Banerjee, Daipayan et al. (2018) cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nat Med 24:50-61
Kochounian, Harold; Zhang, Zhaoxia; Spee, Christine et al. (2016) Targeting of exon VI-skipping human RGR-opsin to the plasma membrane of pigment epithelium and co-localization with terminal complement complex C5b-9. Mol Vis 22:213-23
Ishikawa, Keijiro; Kannan, Ram; Hinton, David R (2016) Molecular mechanisms of subretinal fibrosis in age-related macular degeneration. Exp Eye Res 142:19-25
Sreekumar, Parameswaran G; Ishikawa, Keijiro; Spee, Chris et al. (2016) The Mitochondrial-Derived Peptide Humanin Protects RPE Cells From Oxidative Stress, Senescence, and Mitochondrial Dysfunction. Invest Ophthalmol Vis Sci 57:1238-53
Kannan, Ram; Sreekumar, Parameswaran G; Hinton, David R (2016) Alpha crystallins in the retinal pigment epithelium and implications for the pathogenesis and treatment of age-related macular degeneration. Biochim Biophys Acta 1860:258-68
Ishikawa, Keijiro; Sreekumar, Parameswaran G; Spee, Christine et al. (2016) ?B-Crystallin Regulates Subretinal Fibrosis by Modulation of Epithelial-Mesenchymal Transition. Am J Pathol 186:859-73
Zhang, Huiming; He, Shikun; Spee, Christine et al. (2015) SIRT1 mediated inhibition of VEGF/VEGFR2 signaling by Resveratrol and its relevance to choroidal neovascularization. Cytokine 76:549-552
Chan, Nymph; He, Shikun; Spee, Christine K et al. (2015) Attenuation of choroidal neovascularization by histone deacetylase inhibitor. PLoS One 10:e0120587
Ishikawa, Keijiro; He, Shikun; Terasaki, Hiroto et al. (2015) Resveratrol inhibits epithelial-mesenchymal transition of retinal pigment epithelium and development of proliferative vitreoretinopathy. Sci Rep 5:16386
He, Shikun; Barron, Ernesto; Ishikawa, Keijiro et al. (2015) Inhibition of DNA Methylation and Methyl-CpG-Binding Protein 2 Suppresses RPE Transdifferentiation: Relevance to Proliferative Vitreoretinopathy. Invest Ophthalmol Vis Sci 56:5579-89

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