Retinal neovascularization is the leading cause of blindness in the United States among working-age adults (diabetic retinopathy) and infants (retinopathy of prematurity). An important event of the angiogenesis cascade is the breakdown of the capillary basement membrane and the invasion and migration of microvascular endothelial cells through the extracellular matrix. This step of angiogenesis is partially dependent upon the expression and activity of proteinases, including urokinase (uPA) and its receptor. The activity of this enzyme is regulated by specific endogenous inhibitor, plasminogen activator inhibitor PAI-1. PAI-1 is elevated in the retina during new vessel formation and appears to be required for the neovascular response. The initiation of angiogenesis and the stimulation of proteinase and inhibitor expression are regulated by the activity of specific growth factors including the well known vascular endothelial growth factor (VEGF). Other factors may play important roles during this process including the hepatocyte growth factor (HGF) which has received little attention in terms of its function in ocular angiogenesis. Understanding the mechanisms of proteinase, proteinase inhibitor and growth factor expression, and identifying specific inhibitors of their functions may provide unique opportunities for the development of new therapeutic interventions for retinal neovascularization. This proposal will test the hypothesis that retinal neovascularization is facilitated by the expression of specific growth factors, extracelluar proteinases and their inhibitors, the inhibition of which may lead to new and useful therapies.
The aims of this study which will address the hypothesis are: (1) To characterize the expression and role of PAI-1 in retinal neovascularization. We will use biochemical, histological and molecular techniques, including the use of knockout animals to address this aim. (2) To determine the expression and role of hepatocyte growth factor (HGF) in the regulation of proteinase expression and retinal capillary endothelial cell behavior in retinal neovascularization. Studies will focus on the role of HGF in regulating proteinase expression and endothelial cell behavior using wildtype and transgenic animals. (3) To determine if the extent of retinal neovascularization can be suppressed through the use of agents which directly or indirectly inhibit the function of PAI-1 or HGF. The results of these studies will allow us to further define the mechanisms involved in the formation of new vessels in the retina 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. ? ? ?
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