Continued studies evaluating the mechanistic role of growth factors in the pathogenesis of age-related macular degeneration (AMD) and its blinding complication, choroidal neovascularization (CNV), are proposed. Early AMD, characterized by drusen and degenerative retinal pigment epithelium (RPE) in the macula, progresses to late AMD by following one of two divergent pathways;geographic atrophy is associated with progressive senescence and death of RPE, while CNV is associated with activation and proliferation of the RPE and choroidal endothelial cells (CEC). Our hypothesis is that increased expression of bone morphogenetic protein-4 (BMP4) in RPE induces the senescence and cell death characteristic of dry AMD, and inhibits choroidal angiogenesis. In the presence of inflammation (eg TNF-alpha), BMP4 expression is downregulated resulting in an environment that is permissive for choroidal angiogenesis;co-expression of angiogenic growth factors induces CNV. This hypothesis will be tested using the following Specific Aims: 1. Determine the factors and pathways regulating expression/activity of BMP4 and BMP4 receptors in RPE and CEC, and the mechanisms involved in differential activation of the downstream SMAD and MAPK signaling pathways. 2. Determine the mechanisms involved in BMP4-induced RPE senescence and apoptosis in vitro and in vivo. 3. Determine the role that BMP4 plays in the initiation, promotion and regression of choroidal neovascularization in vitro and in vivo. This project will help to determine whether BMP4 acts as a switch that directs progression of early AMD toward an advanced dry AMD phenotype with geographic atrophy, or towards the wet form of AMD with CNV. If this is true, BMP4 may represent a novel therapeutic target for the treatment of AMD.
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