Continued studies evaluating the mechanistic role of growth factors in the pathogenesis of age-related macular degeneration (AMD) and its blinding complication, choroidal neovascularization (CNV), are proposed. Early AMD, characterized by drusen and degenerative retinal pigment epithelium (RPE) in the macula, progresses to late AMD by following one of two divergent pathways;geographic atrophy is associated with progressive senescence and death of RPE, while CNV is associated with activation and proliferation of the RPE and choroidal endothelial cells (CEC). Our hypothesis is that increased expression of bone morphogenetic protein-4 (BMP4) in RPE induces the senescence and cell death characteristic of dry AMD, and inhibits choroidal angiogenesis. In the presence of inflammation (eg TNF-alpha), BMP4 expression is downregulated resulting in an environment that is permissive for choroidal angiogenesis;co-expression of angiogenic growth factors induces CNV. This hypothesis will be tested using the following Specific Aims: 1. Determine the factors and pathways regulating expression/activity of BMP4 and BMP4 receptors in RPE and CEC, and the mechanisms involved in differential activation of the downstream SMAD and MAPK signaling pathways. 2. Determine the mechanisms involved in BMP4-induced RPE senescence and apoptosis in vitro and in vivo. 3. Determine the role that BMP4 plays in the initiation, promotion and regression of choroidal neovascularization in vitro and in vivo. This project will help to determine whether BMP4 acts as a switch that directs progression of early AMD toward an advanced dry AMD phenotype with geographic atrophy, or towards the wet form of AMD with CNV. If this is true, BMP4 may represent a novel therapeutic target for the treatment of AMD.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY001545-32
Application #
7796676
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
1983-02-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
32
Fiscal Year
2010
Total Cost
$403,425
Indirect Cost
Name
University of Southern California
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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
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
Hirsch, Louis; Nazari, Hossein; Sreekumar, Parameswaran G et al. (2015) TGF-?2 secretion from RPE decreases with polarization and becomes apically oriented. Cytokine 71:394-6
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
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

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