The role of tubedown on the permeability of retinal endothelial cells

Islam, Thasin Jackie (2008) The role of tubedown on the permeability of retinal endothelial cells. Masters thesis, Memorial University of Newfoundland.

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Tubedown (Tbdn) is a mammalian homologue of the N-terminal acetyltransferase subunit NAT1 of S. cerevisiae and copurifies with an acetyltransferase activity. Previous studies have demonstrated a suppression of Tbdn in the retinal blood vessels of patients with neovascular retinopathy including proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP). Moreover, conditional endothelial knockdown of Tbdn in the mouse blood vessel leads to retinal lesions similar to neovascular retinopathy, characterized by abnormal retinal vascular structures, an increase in numbers of retinal blood vessels, and thickening of the retinal tissues. These results indicate that Tbdn is required for retinal homeostasis. Means to restore Tbdn expression and/or activity may be useful for treating neovascular retinopathy. Recent evidence from our lab suggests that Tbdn binds to the actin binding protein cortactin. Tbdn also has been shown to co-localize with the actin cytoskeleton. The actin cytoskeleton is involved in regulating cell permeability and tight junctions. A change in the permeability of endothelial cells has been shown to occur in neovascular PDR. In addition, tight junctions that are important for the blood-retinal barrier are also disrupted during the process of eovascularization. Therefore, this study investigated whether a decreased level of Tbdn increases the permeability of retinal endothelial cell layers. Our results indicate that knockdown of Tbdn expression in endothelial cells leads to a significant increase in cellular permeability measured by transit of FITC-albumin across a monolayer of retinal endothelial cells. Similarly, under in vivo conditions the extravasation of albumin was seen in retinal blood vessels of mice wherein Tbdn was conditionally knocked down in the endothelium. Based on our findings we are proposing a model in which Tbdn act in concert with cortactin to regulate the permeability of FITC-albumin in the retinal endothelial cells via its conserved domains. Our results suggest that loss of Tbdn could have clinically relevant significance and Tbdn may be used as a future drug target.

Item Type: Thesis (Masters)
Item ID: 9368
Additional Information: Includes bibliographical references (leaves 45-57).
Department(s): Medicine, Faculty of
Date: 2008
Date Type: Submission
Library of Congress Subject Heading: Acetyltransferases; Retina--Blood-vessels--Permeability; Vascular endothelium
Medical Subject Heading: Acetyltransferases; Retinal Vessels--metabolism; Permeability

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