Diabetic retinopathy (DR) is an ischemic retinopathy, which has also been described as an inflammatory disorder. DR and other ischemic retinopathies cause significant visual loss through blood-retinal barrier (BRB) breakdown and retinal neovascularization (NV). A number of molecules have been identified that are associated with ischemia and/or are pro-inflammatory and are implicated with the pathogenesis of DR. These molecules include vascular endothelial growth factor (VEGF) and its receptors, placental growth factor (PIGF), and tumor necrosis factor-a (TNFa). VEGF, PIGF, and TNFa are angiogenic and VEGF and TNFa are also pro-inflammatory. VEGF has been identified as a key molecule in mediating the adverse effects of ischemic retinopathies such as DR, retinopathy of prematurity, and branch and central retinal vein occlusions, but PIGF and TNFa have been shown to potentiate the angiogenic and vasopermeability activities of VEGF. Through the use of TNFa knockout mice and a variety of antagonists that operate through different signaling pathways, the roles of these molecules in the pathogenesis of ischemic retinopathies and the pathways involved may be determined. Interrupting the appropriate signaling pathway could impede the progression of DR and other ischemic retinopathies and antagonists of VEGF receptors. TNFa, PIGF, and PKC will be evaluated for this potential. A variety of molecules are associated with DR and other ischemic retinopathies, but due to the complexity of DR, it is unlikely that targeting a single molecule will effectively inhibit BRB breakdown leading to macular edema. If the molecules and pathways that are critical for the adverse effects of DR to develop are identified, they can be used as targets for its treatment. If multiple target molecules are identified, combination therapies can be devised to provide maximum therapeutic effectiveness while minimizing adverse effects.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY017164-02S1
Application #
7905320
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
2007-09-30
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$204,877
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Huang, Hu; Parlier, Rachel; Shen, Ji-Kui et al. (2013) VEGF receptor blockade markedly reduces retinal microglia/macrophage infiltration into laser-induced CNV. PLoS One 8:e71808
Chronopoulos, Argyrios; Trudeau, Kyle; Roy, Sumon et al. (2011) High glucose-induced altered basement membrane composition and structure increases trans-endothelial permeability: implications for diabetic retinopathy. Curr Eye Res 36:747-53
Cai, Jun; Wu, Lin; Qi, Xiaoping et al. (2011) Placenta growth factor-1 exerts time-dependent stabilization of adherens junctions following VEGF-induced vascular permeability. PLoS One 6:e18076
Huang, Hu; Gandhi, Jarel K; Zhong, Xiufeng et al. (2011) TNFalpha is required for late BRB breakdown in diabetic retinopathy, and its inhibition prevents leukostasis and protects vessels and neurons from apoptosis. Invest Ophthalmol Vis Sci 52:1336-44
Huang, Hu; Shen, Jikui; Vinores, Stanley A (2011) Blockade of VEGFR1 and 2 suppresses pathological angiogenesis and vascular leakage in the eye. PLoS One 6:e21411
Huang, Hu; Van de Veire, Sara; Dalal, Mansi et al. (2011) Reduced retinal neovascularization, vascular permeability, and apoptosis in ischemic retinopathy in the absence of prolyl hydroxylase-1 due to the prevention of hyperoxia-induced vascular obliteration. Invest Ophthalmol Vis Sci 52:7565-73
Zhong, Xiufeng; Huang, Hu; Shen, Jikui et al. (2011) Vascular endothelial growth factor-B gene transfer exacerbates retinal and choroidal neovascularization and vasopermeability without promoting inflammation. Mol Vis 17:492-507
Huang, Hu; Vasilakis, Panagiotis; Zhong, Xiufeng et al. (2010) Parstatin suppresses ocular neovascularization and inflammation. Invest Ophthalmol Vis Sci 51:5825-32

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