The goal of this application is to test the hypothesis that the growth and survival of ocular blood vessels depends on a subset of specific vascular endothelial growth factor (VEGF) isoforms and receptors. It is well established that blood vessel growth occurs in association with hypoxia and inflammation, but the molecular mechanisms have not been elucidated. Preliminary data: (1) Corneal VEGF expression increases 10-fold in inflamed cornea and is temporally and spatially correlated with corneal neovascularization. (2) Corneal epithelium and leukocytes express VEGF in inflamed cornea in vivo. (3) Interleukin-1B and hypoxia increase corneal epithelial cell and leukocyte VEGF expression in vitro. (4) Constitutive VEGF expression varies within the eye and is correlated with the survival of new and established non-growing ocular blood vessels. (5) Ribonuclease protection assays have been developed for the quantitation of VEGF isoforms and receptors in ocular tissues. (6) Methods have been developed to investigate the biological actions of the individual VEGF isoforms and receptors in vivo.
Specific aims : (1) To provide direct evidence that short-term and long-term ocular surface blood vessel survival requires VEGF. (2) To directly define the biological actions of the individual VEGF isoforms and receptors in vivo and to localize and quantify their expression in adult eyes. (3) to determine the mechanism and requirement of VEGF induction in inflammation-associated corneal neovasclarization. Significance. These studies may directly identify (i) the first endogenous survival factor for new and established blood vessels in the adult eye; (ii) the specific VEGF isoforms and receptors which mediate its biological actions in vivo; (iii) the first functional endogenous corneal angiogenic factor; (iv) the operative in vivo mechanism(s) which induce VEGF expression in inflamed cornea.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011627-04
Application #
6179096
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
1997-08-01
Project End
2001-01-31
Budget Start
2000-08-01
Budget End
2001-01-31
Support Year
4
Fiscal Year
2000
Total Cost
$80,740
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Poulaki, Vassiliki; Joussen, Antonia M; Mitsiades, Nicholas et al. (2004) Insulin-like growth factor-I plays a pathogenetic role in diabetic retinopathy. Am J Pathol 165:457-69
Yamashiro, Kenji; Tsujikawa, Akitaka; Ishida, Susumu et al. (2003) Platelets accumulate in the diabetic retinal vasculature following endothelial death and suppress blood-retinal barrier breakdown. Am J Pathol 163:253-9
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Joussen, Antonia M; Poulaki, Vassiliki; Mitsiades, Nicholas et al. (2003) VEGF-dependent conjunctivalization of the corneal surface. Invest Ophthalmol Vis Sci 44:117-23
Moore, Tara C B; Moore, Jonathan E; Kaji, Yuichi et al. (2003) The role of advanced glycation end products in retinal microvascular leukostasis. Invest Ophthalmol Vis Sci 44:4457-64
Ishida, Susumu; Yamashiro, Kenji; Usui, Tomohiko et al. (2003) Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease. Nat Med 9:781-8
Joussen, Antonia M; Poulaki, Vassiliki; Qin, Wenying et al. (2002) Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. Am J Pathol 160:501-9
Joussen, Antonia M; Poulaki, Vassiliki; Tsujikawa, Akitaka et al. (2002) Suppression of diabetic retinopathy with angiopoietin-1. Am J Pathol 160:1683-93
Poulaki, Vassiliki; Qin, Wenying; Joussen, Antonia M et al. (2002) Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1alpha and VEGF. J Clin Invest 109:805-15

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