Role of long noncoding RNAs in human ocular angiogenesis

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This project focuses on elucidating the function and mechanism of long noncoding RNAs (lncRNAs) in human ocular angiogenesis. Anti-angiogenic therapies using antibodies to vascular endothelial growth factor (VEGF) have been approved by FDA for cancer treatment and are also the first option of treatment for wet age-related macular degeneration (AMD). However, in many cases, the efficacy of antiangiogenic therapy is still limited, and some patients failed to respond to anti-VEGF treatment. A thorough mechanistic investigation of angiogenesis especially in humans is warranted in order to develop novel and alternative therapeutic approaches. The long- term goal for my laboratory is to decipher the mechanism of noncoding RNAs in ocular vascular development and disease. LncRNAs represent a large group of long (typically >200nt) noncoding RNAs with diverse biological functions, with their roles in angiogenesis still largely unclear. Our genome-wide search has identified a group of human endothelial cell (EC)-enriched lncRNAs. This proposal focuses on a novel primate-specific, EC-enriched lncRNA lncEGFL7OS, which is located in the anti-sense strand of EGFL7/miR-126 gene. Based on our preliminary data and the unique system we recently developed, we test the organizing hypothesis that lncEGFL7OS is required for ocular angiogenesis in humans by regulating the transcription activity of EGFL7/miR- 126. Aim I is to examine the expression and regulation of lncEGFL7OS in ECs. Aim II is to establish a critical role for lncEGFL7OS in human ocular angiogenesis using our unique human angiogenesis system and CRISPR-based technologies. Aim III is to determine the functional mechanism of lncEGFL7OS in angiogenesis.