Diabetic retinopathy has remained the leading cause of blindness in the U.S. since the 1970s. It is manifested by changes in the diabetic eye microvasculature which may progress from background retinopathy to neovascularization and retinal edema. The latter changes cause severe vision disability with resultant high costs for therapy. A major vision-impairing sign of diabetic retinopathy is proliferation of retinal blood vessels. This is possibly induced by elevated angiogenic growth factor. Vascular extracellular matrix and basement membrane also play an important role in this process. However, the role of basement membrane components in diabetic retinal neovascularization and the influence of growth factors on their expression remain obscure. The investigators have studies the expression of many extracellular matrix and basement membrane proteins and growth factors in normal and diabetic human retinas and cultured retinal epithelium. The hypothesis to be tested is that vascular endothelial growth factor stimulates endothelial cell tenascin-C expression and its deposition in retinal neovascular basement membrane. This, in turn, affects the migratory and angiogenic potential of retinal endothelium, thus contributing to the development of diabetic retinal neovascularization.
Specific aims i n this proposal are: 1) To characterize in detain the effect of VEGF on tenascin-C gene and protein expression in retinal endothelial cells in culture. 2) To identify the effects of specific tenascin-C splice variance elevated in diabetic retinopathy on migration, angiogenesis and differentiation of culture retinal endothelium. 3) To attempt to block the VEGF induce migration and angiogenesis in retinal endothelial cultures using neutralizing antibodies to tenascin-C and its binding integrins.
