(Candidate's Abstract) Diseases of the retina and choroid cause most cases of blindness and visual disability in the United States. Abnormal blood vessel growth is the final common pathway to visual loss in many retinal diseases, such as retinopathy of prematurity (ROP), diabetic retinopathy, and sickle cell retinopathy.Despite the prevalence of these diseases, the biochemical events responsible for retinal neovascularization remain to be elucidated. The goal of the proposed research is to improve our understanding of the fundamental pathophysiology of retinal neovascularization so that more effective treatment and prevention for retinal vascular diseases can be developed. To accomplish this goal, the biochemical mechanisms involved in the pathogenesis of retinal neovascularization will be studied using a mouse model of proliferative retinopathy.In this model, mice are exposed to hyperoxia and then returned to room air to induce reproducible and quantifiable retinal neovascularization. Two approaches will be used to study the biochemistry of retinal neovascularization.In Phase I of the proposed research, the hypothesis that the angiogenic factor vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is necessary for normal and pathologic retinal angiogenesis will be tested. The expression of VEGF/VPF during retinal neovascularization will be characterized in detail to determine if VEGF/VPF expression is spatially and temporally correlated with neovascularization. Experiments which attempt to block VEGF/VPF activity will be performed to determine if VEGF/VPF is required for retinal neovascularization. In Phase II a different approach to the study of retinal neovascularization will be used. While it is possible that VEGF/VPF is required for ocular angiogenesis, it is likely that other factors are also involved.Some of the genes that undergo changes in expression in the early stages of retinal neovascularization are likely to be important regulators of pathologic angiogenesis. To identify other genes that undergo changes in expression at the onset of neovascularization the technique of differential display of messenger RNAs will be used. Genes that are confirmed to be up or down regulated in a time course consistent with their having a role in regulating retinal neovascularization will cloned, sequenced and studied in more detail.
| Pierce, E A; Foley, E D; Smith, L E (1996) Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol 114:1219-28 |
| Pierce, E A; Avery, R L; Foley, E D et al. (1995) Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci U S A 92:905-9 |
