Diabetic retinopathy is a leading cause of vision impairment and is exacerbated by hypertension. Vision impairment results from increased retinal vascular permeability and macular edema. The overall goal of this project is to understand how diabetes and hypertension interact to impair vision. The specific objectives are to identify the mechanisms by which chemical (VEGF, angiotensin II) and physical factors (increased hydrostatic pressure) increase retinal vascular permeability. In the initial four years of this project the investigators have shown that VEGF and diabetes alter the expression and phosphorylation of endothelial tight junction proteins concomitant with increased blood-retinal barrier (BRB) permeability. Preliminary studies demonstrate that VEGF, angiotensin II and hyperglycemia impair endothelial cell signaling pathways to tight junctions. In addition, experimental hypertension exerts physical forces on endothelium. The project will investigate the signal transduction pathways by which VEGF, angiotensin II and pressure forces increase BRB permeability. The general hypothesis is proposed that diabetes and hypertension impair blood-retinal barrier integrity via effects on endothelial tight junction proteins.
Three specific aims will test the hypothesis: first, to determine the mechanism by which VEGF regulates tight junction protein phosphorylation and retinal vascular permeability; second, to determine the mechanism by which elevated transmural hydrostatic pressure impairs BRB integrity; and third, to investigate the mechanism by which hypertension accelerates blood-retinal barrier breakdown in diabetic rats. A combination of cell culture, ex vivo and in vivo models will be used. The rationale for this research is that understanding the molecular mechanisms of BRB regulation will provide improved means to control vascular permeability and vision loss in diabetes and other retinal vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012021-09
Application #
7220571
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
1998-09-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
9
Fiscal Year
2007
Total Cost
$324,914
Indirect Cost
Name
Pennsylvania State University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Gonçalves, Andreia; Lin, Cheng-Mao; Muthusamy, Arivalagan et al. (2016) Protective Effect of a GLP-1 Analog on Ischemia-Reperfusion Induced Blood-Retinal Barrier Breakdown and Inflammation. Invest Ophthalmol Vis Sci 57:2584-92

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