May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Identifying Mammalian Proteins That Modulate Angiogenesis in vivo Using a Large Scale Genetic Screen
Author Affiliations & Notes
  • D. S. Rice
    Ophthalmology, Lexicon Pharmaceuticals Inc, The Woodlands, Texas
  • K. Paes
    Ophthalmology, Lexicon Pharmaceuticals Inc, The Woodlands, Texas
  • D. Markesich
    Ophthalmology, Lexicon Pharmaceuticals Inc, The Woodlands, Texas
  • T. Perry
    Ophthalmology, Lexicon Pharmaceuticals Inc, The Woodlands, Texas
  • M. Crist
    Ophthalmology, Lexicon Pharmaceuticals Inc, The Woodlands, Texas
  • W. Walke
    Ophthalmology, Lexicon Pharmaceuticals Inc, The Woodlands, Texas
  • B. Zambrowicz
    Ophthalmology, Lexicon Pharmaceuticals Inc, The Woodlands, Texas
  • Footnotes
    Commercial Relationships  D.S. Rice, Lexicon Pharmaceuticals, E; K. Paes, Lexicon Pharmaceuticals, E; D. Markesich, Lexicon Pharmaceuticals, E; T. Perry, Lexicon Pharmaceuticals, E; M. Crist, Lexicon Pharmaceuticals, E; W. Walke, Lexicon Pharmaceuticals, E; B. Zambrowicz, Lexicon Pharmaceuticals, E.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 522. doi:https://doi.org/
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      D. S. Rice, K. Paes, D. Markesich, T. Perry, M. Crist, W. Walke, B. Zambrowicz; Identifying Mammalian Proteins That Modulate Angiogenesis in vivo Using a Large Scale Genetic Screen. Invest. Ophthalmol. Vis. Sci. 2008;49(13):522. doi: https://doi.org/.

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

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Abstract

Purpose: : Identifying genes that promote blood vessel formation is an important process in the development of new treatments for neovascular eye diseases. We are conducting a large-scale genetic screen using knockout animals to identify genes important in vascular biology. Genetic inhibition of key molecules affecting endothelial cell biology, such as VEGF and Delta-like ligand 4, often results in vascular defects during early embryogenesis. We are conducting a large genetic screen to identify genes important for vascular biology in mammals.

Methods: : Mouse genes are disrupted using high throughput gene-targeting and gene-trapping techniques in embryonic stem (ES) cells. Embryos are harvested at early stages of development, and blood vessel morphology is examined in whole mount preparations. In addition, the potential for these genes to contribute to blood vessel formation and organization is studied in vitro using RNAi knockdown in HUVEC cells and in cultures of targeted ES cells induced to form embryoid bodies.

Results: : We have disrupted over 4,000 genes in mice and have identified hundreds of genes that result in embryonic lethality. Approximately 40% of genes studied in HUVEC assays using RNAi affect network formation. Targeted disruption in ES cells reveals a subset of these genes that affect sprouting angiogenesis in embryoid body assays. Finally, multiple vascular phenotypes have been identified during embryogenesis in vivo.

Conclusions: : Blood vessel formation contributes to neovascular diseases such as wet age-related macular degeneration and also promotes tumor progression. These genetic screens enable the identification of proteins that modulate blood vessel formation, and provide new targets for therapeutic intervention in neovascular diseases.

Keywords: age-related macular degeneration • genetics • choroid 
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