Role of caveolin-1 in the maintenance of blood-retinal barrier integrity

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Project Summary/Abstract Caveolin-1 (Cav-1), the signature protein of caveolae membrane domains, 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, ion homeostasis, and retinal function. More recently, we have found that Cav-1 promotes the activation of Toll-like Receptor-4 (TLR4) propagating TLR4-induced cytokine production and inflammatory BRB breakdown. As Cav-1 is upregulated in several retinal inflammatory conditions, our 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 resulting from pathogens as well as from endogenous damage that occurs during retinal degenerative diseases. However, as Cav-1 plays several important roles in retinal homeostasis and cardiovascular function, we must carefully evaluate the cell and tissue-intrinsic roles of this protein to determine the potential of suppressing Cav-1 function locally in the 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 neurodegeneration induced by inflammation. We will test a novel mechanism whereby Cav-1 modulates the stability of TNF Receptor Associated Factor 3 (TRAF3) a downstream signaling component of innate immune receptors such as TLR4. TRAF3 is abundantly expressed in the retina but has yet to be rigorously studied as a local regulator of immune signaling. The goals of this proposal are to determine the mechanism(s) by which Cav-1 modulates retinal inflammatory signaling, BRB breakdown, and neurodegeneration induced by both pathogen- and damage-derived immune activation. We will also examine the mechanism by which Cav-1 controls retinal TRAF3 levels. These goals have clear