Anti-VEGF therapy is the current mainstay for treating wet age-related macular degeneration (AMD). The efficacy of anti-VEGF therapy is still limited, and some patients failed to respond to the treatment. No drug is currently available for subretinal fibrosis associated with AMD. Therefore, there is a great need for developing alternative or superior approaches to the current anti-VEGF therapy to combat choroidal neovascularization (CNV) and subretinal fibrosis in AMD. Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells can lead to fibrosis. However, the contribution of RPE EMT in AMD pathogenesis remains undefined. MicroRNAs belong to a large group of noncoding RNAs which can regulate diverse pathways in different cell types. The involvement of miRNAs in CNV, RPE EMT and fibrosis remains unclear. This project focuses on elucidating the function and mechanism of miRNAs in the context of complex pathological processes involved in AMD, including CNV, EMT of the RPE cells and fibrosis. The contribution of EMT of RPE cells in AMD mouse models will be examined by genetic lineage tracing. The organizing hypothesis of the proposal is that a single miRNA, miR-24, can repress CNV, EMT of RPEs and fibrosis, therefore representing an excellent “one drug/multiple targets” model for treating AMD. In addition, the contribution of EMT of RPE cells in AMD pathogenesis will also be established. Aim I is to define the function of miR-24 in ocular neovascularization, inflammation and fibrosis. Aim II is to determine the role of miR-24-regulated EMT and fibrosis of RPE cells.