Abstract

Subretinal neovascularization (SRN) is a catastrophic development in many degenerative retinal diseases, including age-related macular degeneration--the most common cause of loss of reading vision among the elderly. Our past studies have been directed to the development and study of animal models of SRN and to perfection of an intraocular cannula system for the prolonged delivery of drugs to the retina. We propose to use this technology to test several different but not mutually exclusive hypotheses concerning the pathogenesis of experimental primate SRN. SRN results from an imbalance between: (1) inhibitory factors produced by the RPE and (2) mitogens, such as cycloxygenase products, produced by macrophages. Tests of these hypotheses include replacement of RPE by transplantation and chronic intravitreal indomethacin. SRN development requires (3) lysis of the extracellular matrix and basement membrane by proteases produced by endothelial sprouts. This will be tested in our SRN model by chronic intravitreal administration of protease inhibitors. SrN also requires (4) laying down of basement membrane. This will be tested with intraocular proline analogs, which inhibit basement membrane formation. The results of these studies may lead us toward a rational drug-based and/or transplant-based therapy for SRN.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY001545-16
Application #
3256009
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1983-02-01
Project End
1996-01-31
Budget Start
1992-02-01
Budget End
1993-01-31
Support Year
16
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of Southern California
Department
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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