Continued studies on basic mechanisms of atrophic age related macular degeneration (AMD) are proposed with translation of this work to establish novel therapies. Early AMD progresses to late blinding forms of the disease by following one of two divergent pathways;atrophic AMD or geographic atrophy (GA) is associated with progressive senescence and death of the retinal pigment epithelium (RPE), while choroidal neovascularization (CNV) is associated with growth of new vessels under the retina. In the last grant period we developed strong support for our hypothesis that increased expression of bone morphogenetic protein-4 (BMP4) in RPE induces features characteristic of atrophic AMD, and inhibits CNV;thus mediating a "molecular switch" that determines which late form of AMD a patient develops. One of the major responses to increased BMP4 expression in RPE is upregulated protein expression of the chaperone aB crystallin. We hypothesize that in early AMD, increased BMP4 expression leads to RPE senescence and a novel reactive neuroprotective response with increased expression of aB crystallin from RPE;however as disease progresses, this response is overwhelmed and further sustained oxidative stress results in progression to GA. We then hypothesize that aB crystallin-derived oligopeptides with chaperone activity can provide similar protection of RPE from oxidative stress and other injuries and can be selectively transported into the RPE. Furthermore, novel aB crystallin peptide nanoparticles can be assembled and optimized to effectively rescue dysfunctional RPE in culture, and in multiple murine models with features of GA. This work is highly significant since there is currently no effective therapy for GA. The hypotheses will be tested using the following Specific Aims:
Aim #1. Determine the molecular, cellular, and functional inter-relationships between BMP4 and aB crystallin in RPE and the effect of oxidative stress on these processes.
Aim # 2. Develop and optimize aB crystallin peptide nanoparticles that inhibit effects of various forms of stress in RPE cells grown in culture.
Aim # 3. Determine the pharmacokinetics of aB crystallin peptide nanoparticles after intraocular or systemic delivery and determine the ability of these nanoparticles to inhibit progression of disease in multiple murine models with features of GA .

Public Health Relevance

Age-related macular degeneration (AMD) is the most common form of blindness in those over age 60. There is no current effective therapy for the dry form of AMD. This grant is focused on establishing new insights into the pathogenesis of dry AMD and translating this knowledge to develop novel therapeutic approaches to the disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY001545-36
Application #
8658070
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
1983-02-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
36
Fiscal Year
2014
Total Cost
$402,719
Indirect Cost
$157,719
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
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
Ishikawa, Keijiro; Sreekumar, Parameswaran G; Spee, Christine et al. (2016) αB-Crystallin Regulates Subretinal Fibrosis by Modulation of Epithelial-Mesenchymal Transition. Am J Pathol 186:859-73
Ishikawa, Keijiro; Kannan, Ram; Hinton, David R (2016) Molecular mechanisms of subretinal fibrosis in age-related macular degeneration. Exp Eye Res 142:19-25
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
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
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 76:549-52
Hirsch, Louis; Nazari, Hossein; Sreekumar, Parameswaran G et al. (2015) TGF-β2 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

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