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 #
5R01EY019494-05
Application #
8580554
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
2013-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2014
Total Cost
$284,796
Indirect Cost
$90,396
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
Reagan, Alaina M; Gu, Xiaowu; Paudel, Sijalu et al. (2018) Age-related focal loss of contractile vascular smooth muscle cells in retinal arterioles is accelerated by caveolin-1 deficiency. Neurobiol Aging 71:1-12
Tarantini, Stefano; Valcarcel-Ares, M Noa; Yabluchanskiy, Andriy et al. (2018) Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype. J Gerontol A Biol Sci Med Sci 73:853-863
McClellan, Mark E; Elliott, Michael H (2017) Analysis of Fatty Acid and Cholesterol Content from Detergent-Resistant and Detergent-Free Membrane Microdomains. Methods Mol Biol 1609:185-194
Oliveira, Suellen D S; Castellon, Maricela; Chen, Jiwang et al. (2017) Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-?-driven pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 312:L760-L771
Gu, Xiaowu; Reagan, Alaina M; McClellan, Mark E et al. (2017) Caveolins and caveolae in ocular physiology and pathophysiology. Prog Retin Eye Res 56:84-106
Du, Mei; Mangold, Colleen A; Bixler, Georgina V et al. (2017) Retinal gene expression responses to aging are sexually divergent. Mol Vis 23:707-717
Masser, Dustin R; Otalora, Laura; Clark, Nicholas W et al. (2017) Functional changes in the neural retina occur in the absence of mitochondrial dysfunction in a rodent model of diabetic retinopathy. J Neurochem 143:595-608
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
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
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

Showing the most recent 10 out of 23 publications