Geographic atrophy (GA) is an untreatable advanced form of age-related macular degeneration (AMD) that is characterized by degeneration of the retinal pigmented epithelium (RPE). Neither the mechanisms that promote this RPE degeneration nor the basis for the centrifugal expansion of GA that can ultimately lead to blindness have been resolved. This enigmatic nature of GA pathogenesis has precluded the development of any FDA-approved therapy for the one million Americans diagnosed with GA and the millions more at risk of developing GA. In new and exciting studies, we made the surprising observation that there is an abundance of Alu repetitive RNA in the RPE of human eyes with GA that accumulates in response to a dramatic deficiency in the RNase DICER1 and induces RPE degeneration (Kaneko et al. Nature 2011). Our findings, which introduce a novel cell survival function for DICER1 independent of its canonical miRNA biogenesis function and the concept that Alu RNA can directly promote human pathology, provide new mechanistic insights into GA pathogenesis. However, we still lack an integrated understanding of how DICER1 is dysregulated in GA and precisely how Alu RNA induces RPE degeneration. A rigorous definition of these mechanisms is crucial to enhancing our understanding of the molecular drivers of GA and to developing rational treatments. We will provide novel functional insights into how DICER1/Alu RNA dysregulation contributes to GA pathogenesis and develop a novel therapeutic strategy via the following Aims: (1) Generate a spatiotemporal map of DICER1 and Alu RNA in relation to the locus of pathology in GA and early AMD eyes; (2) Decipher the mechanisms by which Alu RNA triggers a new inflammatory cell death pathway we have identified; (3) Define the molecular regulation of DICER1 in the RPE in the context of GA and the function of a novel DICER1 splice variant; (4) Create a new animal model of GA having human-like features of the disease and validate an antisense therapeutic strategy targeting Alu RNA. These studies will illuminate novel aspects of the molecular and biochemical bases of GA, and help validate a molecular targeting strategy that could be translated into clinical trials. As such, this proposal is perfectly aligned with the 5-year goals of the NEI's Retinal Diseases Program strategic plan.