Retinopathy of prematurity (ROP) is a disorder of pathological retinal neovascularization, which can result in life-long blindness. The long-term goal of this project is to acquire a better understanding of the mechanisms surrounding retinal neovascularization in order to develop anti-angiogenesis therapies. The objective of the current proposal is to determine cells and factors that promote regression of retinal neovascularization. We hypothesize that directly modulating pre-retinal endothelial cell (EC) apoptosis will be an efficient anti-angiogenic approach despite the multiple factors that can promote pathological angiogenesis. We have recently shown that Fas ligand-deficient mice exhibit increased neovascularization and reduced vascular tuft apoptosis in a model of oxygen-induced retinopathy (OIR), supporting a role for FasL in controlling neovascularization. Our preliminary data also suggest that microglial cells/macrophages are potential candidates for regulators of EC apoptosis. A novel class of signaling molecules, the ephrin/Eph receptors are also candidate molecules to regulate EC neovascularization and apoptosis. In order to test our hypothesis and identify mechanisms that are responsible for vascular tuft apoptosis, we propose the following Specific Aims: 1) Identify specific death receptors that lead to EC apoptosis and promote tuft regression, specifically determine if direct activation of Fas will induce vessel regression; 2) Identify the contribution of microglia and macrophages to the regression of retinal neovascularization and their ability to induce apoptosis through the use of genetically altered mice; and 3) Further understand the role of ephrin/Eph receptors in retinal neovascularization. Develop new therapeutic approaches to induce vessel regression, using soluble ligands to modulate the ephrins/Eph receptors in the mouse model of OIR. Our studies should provide insight into the critical link between angiogenesis and apoptosis, providing new avenues of treatment of ischemic retinopathies. ? ?
| Davies, Michael H; Stempel, Andrew J; Hubert, Kristin E et al. (2010) Altered vascular expression of EphrinB2 and EphB4 in a model of oxygen-induced retinopathy. Dev Dyn 239:1695-707 |
| Davies, Michael H; Zamora, David O; Smith, Justine R et al. (2009) Soluble ephrin-B2 mediates apoptosis in retinal neovascularization and in endothelial cells. Microvasc Res 77:382-6 |
| Hubert, Kristin E; Davies, Michael H; Stempel, Andrew J et al. (2009) TRAIL-deficient mice exhibit delayed regression of retinal neovascularization. Am J Pathol 175:2697-708 |
| Davies, Michael H; Stempel, Andrew J; Powers, Michael R (2008) MCP-1 deficiency delays regression of pathologic retinal neovascularization in a model of ischemic retinopathy. Invest Ophthalmol Vis Sci 49:4195-202 |
