IN VIVO ROLE OF CAVEOLIN-1 IN MODULATING PHOTORECEPTOR FUNCTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Loss of the blood-retinal barrier (BRB) is a common pathology of age-related macular degeneration (AMD), diabetic retinopathy, and retinopathy of prematurity. Evidence from our laboratory indicates that caveolin-1 (Cav-1), an integral protein component of specialized lipid microdomains called caveolae, is essential for normal retinal function. We observed reduced retinal function in Cav-1 null mice as indicated by electroretinography (ERG) suggesting a photoreceptor defect. However, this reduced photoreceptor function cannot be explained by a direct effect on phototransduction as responses were normal in suction electrode recordings from isolated Cav-1 null rods. This has led us to propose that alterations in the local photoreceptor environment results in the observed functional deficit. In support of this hypothesis, we have data demonstrating loss of BRB in Cav-1 null mice and significant changes in the extracellular matrix. The increased permeability correlates with alterations in tight junctions and specifically, occludin localization. Furthermore, when subjected to a stress paradigm (oxygen-induced retinopathy), Cav-1 null mice displayed severe retinal hemorrhaging indicating complete BRB breakdown. These results clearly indicate that Cav-1 expression is essential for BRB integrity. In RPE cells, caveolae display a unique bipolar localization both apically (atypical localization) and basolaterally (typical localization) suggesting potential novel function(s) of caveolar domains in RPE. The goals of this COBRE project are to examine the mechanism(s) by which Cav-1 regulates BRB integrity in the RPE. These goals are aligned with a planned R01 submission and their accomplishment will provide essential data to strengthen this application.