Molecular mechanisms of choroidal neovascularization and vascular homeostasis

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DESCRIPTION (provided by applicant): Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide. Our long-term goal is to elucidate the molecular mechanisms that regulate choroidal vascular development, choroidal vascular homeostasis in the adult, and CNV. Understanding these mechanisms is likely to provide the basis for a more targeted therapeutic approach in patients with neovascular AMD. Recent experimental and clinical data have provided strong evidence for a pathogenetic role of VEGF signaling in CNV. Anti-VEGF treatments have shown clinical benefit in reducing CNV in patients with neovascular AMD. However, the molecular mechanisms through which VEGF stimulates CNV in the eye are only poorly understood. Our proposed experiments are directed towards a comprehensive analysis of the individual contributions of VEGF and the VEGF-receptors Flt1 and Flk1 for choroidal vascular functions, and towards exploring these signaling pathways as molecular targets for novel therapeutic approaches in the treatment of neovascular AMD. For this purpose, we will perform experiments that use a combination of conditional gene targeting approaches and treatments with blocking antibodies in mice. We will test the role of VEGF, Flt1 and Flk1 for choroidal endothelial cell functions. Furthermore, we will use an established experimental model for CNV in mice to investigate the role of VEGF and its receptors for CNV. In addition, we will perform GFP-positive bone marrow transplantation experiments and macrophage depletion experiments in order to determine the cellular composition of experimental CNV lesions and to study the effect of antibodies that target VEGF signaling pathways on these cells in this model. PUBLIC HEALTH RELEVANCE: Choroidal neovascularization in age-related macular degeneration is one of the leading causes of blindness worldwide, but only little is known about the molecular mechanisms that result in this abnormal neovascularization in the eye. The goal of the proposed studies is to investigate the role of VEGF signaling for the development, vascular homeostasis and pathological neovascularization of the choroidal vasculature. These findings are likely to reveal novel molecular targets for the treatment of neovascular age-related macular degeneration.