Abstract/Summary Aberrant ocular neovascularization contribute to blindness in numerous conditions including age- related macular degeneration (AMD), diabetic retinopathy, and retinopathy of prematurity. DICER1 is a RNase that processes micro-RNAs and SINE RNAs. Deficiency of DICER1 is implicated in outer retinal pathologies, including choroidal neovascularization. This claim is supported by recently published studies finding that multiple models of DICER1 deficiency develop aberrant choroidal neovascularization in mice, and new evidence that DICER1 expression is significantly reduced in human neovascular AMD. However, major gaps in knowledge persist with respect to the relative contributions of major DICER1 substrate classes micro-RNA and SINE RNA imbalances as contributors to choroidal neovascularization. In addition, whether DICER1 deficiency impedes conventional gene silencing strategies, and the role of DICER1 in age-related neovascular pathologies are unknown. The overall hypothesis of this project is that age-related DICER1 deficiency drives chorioretinal neovascularization via SINE RNA accumulation and impedes conventional gene silencing strategies. We will test this hypothesis in three specific aims. 1) We will distinguish between the contributions of micro-RNA and SINE RNA-dependent processing activities of DICER1 with respect to development and severity of CNV. 2) We will adapt DICER1-independent gene silencing strategies and compare them to traditional DICER1-dependent strategies in models of CNV. 3) We will quantify DICER1 in aging retina, and determine whether ectopic DICER1 expression improves CNV outcomes in aged animals. Collectively, these thematically related, but independent aims will establish new foundational and translationally relevant knowledge about the mediators and consequences of DICER1 deficiency in pathological choroidal neovascularization. These studies may thereby open new interventional avenues for prevalent blinding conditions.