Caveolin-1 (Cav-1), the signature protein of caveolae membrane microdomains, is linked to several ocular/retinal diseases including primary open angle glaucoma, diabetic retinopathy, and autoimmune uveitis. We have found that Cav-1 and caveolae play important roles in blood-retinal barrier (BRB) integrity, retinal ion homeostasis, and retinal function. More recently, we have found that Cav-1 plays a prominent role in promoting retinal inflammatory signaling and inflammatory BRB breakdown. These results imply that local disruption of Cav-1 function presents a viable therapy to suppress retinal inflammatory insults. Given that current steroid- based therapies for retinal inflammatory disease are not completely effective and fraught with potentially severe side effects, we hypothesize that Cav-1 and caveolae domains represent novel therapeutic targets to suppress retinal inflammation. In order to effectively evaluate the therapeutic potential of suppressing Cav-1 function locally in th retina, it is imperative to understand the mechanisms for these complex cell-intrinsic properties. In this proposal we will use cell-specific Cav-1 knockout mice to test cell-intrinsic Cav-1 functions in the hope of validating Cav-1 as a new therapeutic target for retinal inflammation, BRB breakdown, and inflammatory angiogenesis.
The specific aims of this proposal are: 1) to determine which Cav-1-expressing cells promote retinal inflammatory signaling and BRB breakdown, in vivo; 2) to test the mechanism by which Cav-1 modulates inflammatory signaling and BRB breakdown in two disease relevant models, endotoxin- induced uveitis and acute ocular hypertension and; 3) to test preclinical therapeutic strategies to locally disrupt Cav-1-dependent inflammatory signaling and BRB breakdown. These goals have clear

Public Health Relevance

in that we will test a novel therapeutic concept that could make significant impact in improving therapeutic outcomes for the inflammatory pathologies of most major blinding eye diseases. PUBLIC HEALTH RELEVANCE: Inflammation-induced retinal injury and blood-retinal barrier breakdown play critical roles in major blinding eye diseases including glaucoma, diabetic retinopathy, and age-related macular degeneration. Current steroid- based therapies for retinal inflammatory disease are ineffective have serious complications. The goal of this project is to test a novel therapeutic mechanism that could make significant impact in improving therapeutic outcomes for the inflammatory pathologies of major blinding eye diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY019494-06A1
Application #
8963726
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
2009-04-01
Project End
2016-09-29
Budget Start
2015-09-30
Budget End
2016-09-29
Support Year
6
Fiscal Year
2015
Total Cost
$367,788
Indirect Cost
$117,788
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
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
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
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

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