The blood-retinal barrier is essential for normal retinal function and loss of this barrier contributes to the pathophysiology of retinopathy of prematurity, diabetic retinopathy, age related macular degeneration and other retinal diseases. Further, pathological angiogenesis produces highly permeable vessels that lack a proper blood-retinal barrier. The blood vessels of the retina and the retinal pigment epithelium possess well-developed tight junctions that control the flow of fluids and blood-borne solutes into the retina. Induction of the vascular component of the blood-retinal barrier occurs through endothelial interaction with glia and pericytes in vivo and may be induced pharmacologically with glucocorticoids. However, the molecular mechanisms that control tight junction gene expression in the blood-retinal barrier remain largely unexplored. Our overall goal is to understand the process of barrier induction so that novel therapies may be developed to restore the blood-retinal barrier in retinal diseases with limited adverse side effects. The claudins and occludin are transmembrane tight junction proteins necessary for proper formation and regulation of the blood-retinal barrier. Claudin-5 is particularly important to the blood-retinal barrier since this claudin is largely restricted to the vasculature and gene deletion studies have demonstrated claudin-5 is an essential component of the blood-brain and blood-retinal barrier. Occludin content correlates well with barrier integrity, whereas occludin phosphorylation is associated with increased permeability. Our previous studies have demonstrated that glucocorticoids induce gene expression of claudin-5 and occludin and promote barrier integrity. Further, a novel cis-element termed the occludin enhancer element or OEE controls glucocorticoid induction of occludin gene expression. In this proposal we hypothesize that a novel trans-acting transcription factor interacts with the OEE to induce the endothelial cell barrier. These studies will determine the contribution of the OEE element to glucocorticoid control of claudin-5 gene expression, investigate the contribution of the OEE element to RPE expression of tight junction genes and, most importantly, identify the trans-acting factor that controls tight junction gene expression through the OEE. These studies will lead to future investigations that will elucidate the mechanisms of barrier induction during development and advance novel therapies to restore the blood-retinal barrier in disease states.
The blood-retinal barrier is essential for normal retinal function and loss of this barrier contributes to the pathophysiology of retinopathy of prematurity, diabetic retinopathy, age related macular degeneration and other retinal diseases. Further, pathological angiogenesis leads to highly permeable vessels that lack a proper blood-retinal barrier. In this application, we propose a novel molecular mechanism exists to control induction of the blood retinal-barrier. Understanding this mechanism will lead to new therapies to restore the blood-retinal barrier in retinal vascular diseases, with limited side effects.
|Keil, Jason M; Liu, Xuwen; Antonetti, David A (2013) Glucocorticoid induction of occludin expression and endothelial barrier requires transcription factor p54 NONO. Invest Ophthalmol Vis Sci 54:4007-15|