The blood-retinal barrier (BRB) selectively and tightly regulates the local environment of the neural retina. Loss of BRB integrity is a common pathology in three major causes of blindness: diabetic retinopathy;age- related macular degeneration;and retinopathy of prematurity. Recent evidence indicates that caveolin-1 (Cav- 1), an integral protein component of specialized lipid microdomains called caveolae, is essential for normal retinal function. Cav-1 null mice display reduced retinal function in Cav-1 null mice as indicated by electroretinography (ERG) that suggested at a photoreceptor defect. However, this reduced photoreceptor function could not be explained by a direct effect on phototransduction as responses were normal in recordings from isolated Cav-1 null rods. This suggests that the functional deficit in Cav-1 null retinas results from an abnormal local environment surrounding photoreceptors. In support of this hypothesis, compelling evidence indicates that Cav-1 null mice have a hyperpermeable BRB. The increased permeability correlates with alterations in tight junctions, changes in Na/K-ATPase activity, and outer retinal edema. Cav-1 null mice provide compelling data showing a clear loss of retinal pigment epithelial and vascular barrier functions. This increased permeability alters the normal photoreceptor environment which is consistent with reduced retinal function and age-related retinal degeneration observed in these mice. Furthermore, when subjected to a stress paradigm (oxygen-induced retinopathy), Cav-1 null mice display severe subretinal and intraretinal hemorrhaging. These findings clearly indicate that Cav-1 expression/function is essential for the maintenance of a robust BRB but the mechanism(s) of this regulation is unknown.
The first aim i s designed to determine the role of Cav-1 in regulating barrier activity specifically within the retinal pigment epithelium using cell-specific, inducible genetic deletion.
The second aim will test the role of Cav-1 in the structural organization of lipids and proteins in epithelial cell-cell contacts and apical process.
The final aim will focus on the role that dysregulation of the Na/K-ATPase plays and how Cav-1 regulates ATPase activity.

Public Health Relevance

Loss of blood-retinal barrier integrity is a common pathology in three major causes of blindness: diabetic retinopathy;age-related macular degeneration;and retinopathy of prematurity. This project is designed to study mechanisms that regulate blood-retinal barrier integrity to define novel potential therapeutic strategies to ameliorate pathological blood-retinal barrier permeability.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019494-03
Application #
8197255
Study Section
Special Emphasis Panel (ZRG1-CB-G (90))
Program Officer
Neuhold, Lisa
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$346,680
Indirect Cost
$100,440
Name
University of Oklahoma Health Sciences Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Gu, Xiaowu; Fliesler, Steven J; Zhao, You-Yang et al. (2014) Loss of caveolin-1 causes blood-retinal barrier breakdown, venous enlargement, and mural cell alteration. Am J Pathol 184:541-55
Li, Xiaoman; Gu, Xiaowu; Boyce, Timothy M et al. (2014) Caveolin-1 increases proinflammatory chemoattractants and blood-retinal barrier breakdown but decreases leukocyte recruitment in inflammation. Invest Ophthalmol Vis Sci 55:6224-34
Bennett, Lea D; Brush, Richard S; Chan, Michael et al. (2014) Effect of reduced retinal VLC-PUFA on rod and cone photoreceptors. Invest Ophthalmol Vis Sci 55:3150-7
Gu, Xiaowu; Reagan, Alaina; Yen, Allen et al. (2014) Spatial and temporal localization of caveolin-1 protein in the developing retina. Adv Exp Med Biol 801:15-21
Ding, Lexi; Cheng, Rui; Hu, Yang et al. (2014) Peroxisome proliferator-activated receptor ? protects capillary pericytes in the retina. Am J Pathol 184:2709-20
Chen, Hui; Tran, Julie-Thu A; Eckerd, Annette et al. (2013) Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration. J Lipid Res 54:1616-29
Li, Xiaoman; McClellan, Mark E; Tanito, Masaki et al. (2012) Loss of caveolin-1 impairs retinal function due to disturbance of subretinal microenvironment. J Biol Chem 287:16424-34
Mandal, Md Nawajes A; Moiseyev, Gennadiy P; Elliott, Michael H et al. (2011) Alpha-phenyl-N-tert-butylnitrone (PBN) prevents light-induced degeneration of the retina by inhibiting RPE65 protein isomerohydrolase activity. J Biol Chem 286:32491-501
Wang, Juanjuan; Xu, Xueliang; Elliott, Michael H et al. (2010) Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage. Diabetes 59:2297-305