Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. The overwhelming cause of severe vision loss in these patients is choroidal neovascularization (CNV), the growth of abnormal blood vessels beneath the retina. The mechanisms responsible for this process have been deduced to angiogenesis, the sprouting of new blood vessels from pre-existing vasculature, and vasculogenesis, the recruitment, proliferation and incorporation of bone marrow-derived progenitor cells into nascent vasculature. Vascular endothelial growth factor-A (VEGF-A) is a critical mediator in both these pathways and is the target for many FDA approved therapies for CNV. Using the mouse model of laser-induced CNV, we recently discovered a paradoxical effect whereby both endogenous and exogenous VEGF-A suppressed CNV during the acute phase after laser-injury, whereas before injury they enhanced CNV consistent with dogma. We determined that the matricellular protein SPARC/osteonectin constitutively interacts with VEGF-A and prevents it from activating VEGF receptor (VEGFR)-1. Because SPARC levels decline transiently after injury, VEGF-A activates an anti-angiogenic pathway through VEGFR-1 binding and subsequent dephosphorylation of VEGFR-2, the principal signaling receptor that promotes neovascularization. VEGF-A also downregulated the expression of monocyte chemoattractant protein-1 (Ccl-2), which suppressed cell-mediated inflammation and subsequent CNV. The molecular basis of the vexing macular predilection for CNV in humans is unknown;however the spatial confinement of SPARC in the macula of monkey retina is intriguing as a potential underpinning for this phenomenon.
The specific aims of this proposal are to further define the interaction of SPARC and VEGF-A in experimental CNV, determine the precise anti-angiogenic and anti-vasculogenic mechanisms of VEGF-A induced CNV suppression, evaluate the efficacy of modulating SPARC in a non-human primate model of CNV, and define the expression and activity profiles of SPARC and VEGF-A and its receptors in human retina and choroid. Our long term goal is to fully characterize the SPARC-VEGF-A pathway in CNV and identify novel targets for the treatment of this blinding condition which constitutes nothing short of a public health epidemic.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY018350-04S1
Application #
8145754
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
2007-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$89,800
Indirect Cost
Name
University of Kentucky
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Yasuma, Reo; Cicatiello, Valeria; Mizutani, Takeshi et al. (2016) Intravenous immune globulin suppresses angiogenesis in mice and humans. Signal Transduct Target Ther 1:
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Gelfand, Bradley D; Wright, Charles B; Kim, Younghee et al. (2015) Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome. Cell Rep 11:1686-93
Mizutani, Takeshi; Fowler, Benjamin J; Kim, Younghee et al. (2015) Nucleoside Reverse Transcriptase Inhibitors Suppress Laser-Induced Choroidal Neovascularization in Mice. Invest Ophthalmol Vis Sci 56:7122-9
Kim, Younghee; Tarallo, Valeria; Kerur, Nagaraj et al. (2014) DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration. Proc Natl Acad Sci U S A 111:16082-7
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Fowler, Benjamin J; Gelfand, Bradley D; Kim, Younghee et al. (2014) Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 346:1000-3

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