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
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Gu, Xiaowu; Reagan, Alaina M; McClellan, Mark E et al. (2016) Caveolins and caveolae in ocular physiology and pathophysiology. Prog Retin Eye Res :
Sethna, Saumil; Chamakkala, Tess; Gu, Xiaowu et al. (2016) Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision. J Biol Chem 291:6494-506
Yu, Jeremy Y; Du, Mei; Elliott, Michael H et al. (2016) Extravascular modified lipoproteins: a role in the propagation of diabetic retinopathy in a mouse model of type 1 diabetes. Diabetologia 59:2026-35
Ding, Xi-Qin; Thapa, Arjun; Ma, Hongwei et al. (2016) The B3 Subunit of the Cone Cyclic Nucleotide-gated Channel Regulates the Light Responses of Cones and Contributes to the Channel Structural Flexibility. J Biol Chem 291:8721-34
Coburn, Phillip S; Wiskur, Brandt J; Miller, Frederick C et al. (2016) Bloodstream-To-Eye Infections Are Facilitated by Outer Blood-Retinal Barrier Dysfunction. PLoS One 11:e0154560
Elliott, Michael H; Ashpole, Nicole E; Gu, Xiaowu et al. (2016) Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma. Sci Rep 6:37127
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
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
Ding, Lexi; Cheng, Rui; Hu, Yang et al. (2014) Peroxisome proliferator-activated receptor α protects capillary pericytes in the retina. Am J Pathol 184:2709-20

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