May 2004
Volume 45, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2004
Conditional knock–down of Tubedown–1 in endothelial cells in mice leads to retinal neovascular lesions mimicking human proliferative retinopathy
Author Affiliations & Notes
  • H. Paradis
    HSC Faculty of Medicine, Mem Univ Newfoundland, St John's, NF, Canada
  • D.S. Wall
    HSC Faculty of Medicine, Mem Univ Newfoundland, St John's, NF, Canada
  • W.V. Good
    Smith Kettlewell Eye Research Institute, San Francisco, CA
  • E. Miskiewicz
    HSC Faculty of Medicine, Mem Univ Newfoundland, St John's, NF, Canada
  • M. Woodland
    HSC Faculty of Medicine, Mem Univ Newfoundland, St John's, NF, Canada
  • K. LeBlanc
    HSC Faculty of Medicine, Mem Univ Newfoundland, St John's, NF, Canada
  • R.L. Gendron
    HSC Faculty of Medicine, Mem Univ Newfoundland, St John's, NF, Canada
  • Footnotes
    Commercial Relationships  H. Paradis, None; D.S. Wall, None; W.V. Good, None; E. Miskiewicz, None; M. Woodland, None; K. LeBlanc, None; R.L. Gendron, None.
  • Footnotes
    Support  CIHR, FFB–C, NIH
Investigative Ophthalmology & Visual Science May 2004, Vol.45, 464. doi:
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      H. Paradis, D.S. Wall, W.V. Good, E. Miskiewicz, M. Woodland, K. LeBlanc, R.L. Gendron; Conditional knock–down of Tubedown–1 in endothelial cells in mice leads to retinal neovascular lesions mimicking human proliferative retinopathy . Invest. Ophthalmol. Vis. Sci. 2004;45(13):464.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: Tubedown–1 (Tbdn–1) is a novel mouse protein which shows homology to the yeast N–terminal acetyltransferase subunit NAT1 and co–purifies with an acetyltransferase activity. Although expressed at high levels in the developing vasculature, Tbdn–1 expression becomes highly restricted postnatally with expression being maintained in several specialized endothelia, including ocular endothelium, in normal adults. Recent studies have shown that Tbdn–1 is specifically suppressed in retinal endothelial cells from patients with proliferative diabetic retinopathy and that its expression inhibits angiogenesis of choroid/retina endothelial cells in vitro. The present study was designed to provide an in vivo test of our hypothesis that the maintenance of Tbdn–1 expression may be important for retinal vessel homeostasis and for controlling retinal neovascularization in adults. Methods: We generated a bitransgenic mouse model enabling conditional knock–down of Tbdn–1 in endothelial cells. Conditional suppression of Tbdn–1 was achieved using a tetracycline inducible antisense TBDN–1 expression system in combination with the endothelial specific tie–2 promoter. Tbdn–1 suppressed mice were analyzed for Tbdn–1 expression, retinal pathological changes and disturbances in markers for retinal extracellular matrix constituents and macroglia. Results: Transgenic mice with knocked–down Tbdn–1 protein expression in retinal endothelium develop intra and preretinal fibrovascular lesions and retinal neovascularization reminiscent of the pathology observed in human proliferative retinopathies. Retinal lesions observed in knocked–down animals increase in severity with prolonged suppression of Tbdn–1 expression. Moreover, the retinal lesions exhibit abnormal expression patterns of several extracellular matrix components and increases in numbers of glial cells compared to normal retina. Conclusion: The maintenance of Tbdn–1 expression is important for retinal vessel homeostasis and for controlling retinal neovascularization in adults. Understanding the mechanisms through which Tbdn–1 suppresses retinal blood vessel growth could lead to new molecular based therapies for proliferative retinopathies, which remain leading causes of blindness in western populations. CR: N.

Keywords: retinal neovascularization • transgenics/knock–outs • protein modifications–post translational 
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