Retinal neovascularization is the leading cause of blindness in the United States among working-age adults (diabetic retinopathy) and infants (retinopathy of prematurity). Choroidal neovascularization occurs in cases of age-related macular degeneration, the most common cause of blindness in individuals over the age of 60. Although the exact mechanisms leading to the development of new vessels in retinal and choroidal angiogenesis may be different and poorly understood, a common event in both cases is the breakdown of the capillary basement membrane and the invasion and migration of microvascular endothelial cells through the extracellular matrix. The process of angiogenesis is dependent upon the expression of the serine proteinase urokinase and its receptor as well as specific members of the matrix metalloproteinase (MMP) family of enzymes. Understanding the mechanisms of proteinase expression and identifying inhibitors of their function may therefore provide unique opportunities for the development of therapeutic interventions for retinal and choroidal neovascularization. This application will test the hypothesis that retinal and subretinal neovascularization is facilitated by the expression of specific extracelluar proteinases, the inhibition of which may lead to new and useful therapies.
The aims of this study which will address the hypothesis are (1) To further characterize the role of extracellular proteinases and their inhibitors in well established models of retinal and choroidal neovascularization. We will use biochemical, histological and molecular techniques, including the use of knockout animals, to address this aim. (2) To determine the factors and mechanisms which regulate the expression of proteinases in the retina and choroid. Studies will focus on the role of tumor necrosis factor alpha (TNFalpha) and angiopoietin 2 (Ang2) in the regulation of proteinase expression, alone or in combination with other growth factors and a hypoxic stimulus. (3) To determine if the extent of retinal and choroidal neovascularization can be reduced through the use of specific compounds which directly or indirectly affect proteinase expression and/or activity. The results of these studies will allow us to further define the mechanisms involved in the formation of new vessels in the retina and choroid which can lead to serious visual complications, and whether a specific stage of the angiogenic process is an appropriate target for therapeutic intervention. Such an approach will provide a rational basis for the development of potentially powerful and effective therapeutics for ocular neovascularization.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012604-05
Application #
6623635
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Dudley, Peter A
Project Start
1998-09-30
Project End
2006-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
5
Fiscal Year
2003
Total Cost
$300,000
Indirect Cost
Name
University of New Mexico
Department
Surgery
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Rangasamy, Sampathkumar; Srinivasan, Ramprasad; Maestas, Joann et al. (2011) A potential role for angiopoietin 2 in the regulation of the blood-retinal barrier in diabetic retinopathy. Invest Ophthalmol Vis Sci 52:3784-91
McGuire, Paul G; Rangasamy, Sampathkumar; Maestas, Joann et al. (2011) Pericyte-derived sphingosine 1-phosphate induces the expression of adhesion proteins and modulates the retinal endothelial cell barrier. Arterioscler Thromb Vasc Biol 31:e107-15
Basu, Anupam; Menicucci, Gina; Maestas, Joann et al. (2009) Plasminogen activator inhibitor-1 (PAI-1) facilitates retinal angiogenesis in a model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 50:4974-81
Navaratna, Deepti; Menicucci, Gina; Maestas, Joann et al. (2008) A peptide inhibitor of the urokinase/urokinase receptor system inhibits alteration of the blood-retinal barrier in diabetes. FASEB J 22:3310-7
Navaratna, Deepti; Maestas, Joann; McGuire, Paul G et al. (2008) Suppression of retinal neovascularization with an antagonist to vascular endothelial cadherin. Arch Ophthalmol 126:1082-8
Navaratna, Deepti; McGuire, Paul G; Menicucci, Gina et al. (2007) Proteolytic degradation of VE-cadherin alters the blood-retinal barrier in diabetes. Diabetes 56:2380-7
Colombo, Elizabeth S; Menicucci, Gina; McGuire, Paul G et al. (2007) Hepatocyte growth factor/scatter factor promotes retinal angiogenesis through increased urokinase expression. Invest Ophthalmol Vis Sci 48:1793-800
Das, Arup; McGuire, Paul (2006) Role of urokinase inhibitors in choroidal neovascularization. Semin Ophthalmol 21:23-7
Giebel, Stephen J; Menicucci, Gina; McGuire, Paul G et al. (2005) Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood-retinal barrier. Lab Invest 85:597-607
Das, Arup; Boyd, Nathan; Jones, Terence R et al. (2004) Inhibition of choroidal neovascularization by a peptide inhibitor of the urokinase plasminogen activator and receptor system in a mouse model. Arch Ophthalmol 122:1844-9

Showing the most recent 10 out of 17 publications