Role of long noncoding RNAs in human ocular angiogenesis

本项目致力于阐明长链非编码RNA的功能和作用机制 （lncRNA）在人眼部血管生成中的作用。使用抗血管生成抗体的抗血管生成疗法 内皮生长因子（VEGF）已被FDA批准用于癌症治疗， 湿性年龄相关性黄斑变性（AMD）的首选治疗方案。但在许多 例，抗血管生成治疗的疗效仍然有限，部分患者无效 抗VEGF治疗。血管生成的彻底机制研究，特别是在 为了开发新的和替代的治疗方法，人类是有必要的。很长的- 我实验室的长期目标是破译眼血管中非编码RNA的机制， 发展和疾病。lncRNA代表了一大群长的（通常> 200 nt）非编码RNA。 RNA具有多种生物学功能，其在血管生成中的作用仍不清楚。我们 全基因组搜索已经鉴定了一组人内皮细胞（EC）富集的lncRNA。 该提案集中于一种新的灵长类特异性的、EC富集的lncRNA lncEGFL 7 OS， 位于EGFL 7/miR-126基因的反义链。根据我们的初步数据和 我们最近开发的独特系统，我们测试了组织假设，lncEGFL 7 OS是 通过调节EGFL 7/miR-1的转录活性， 126.目的研究lncEGFL 7 OS在内皮细胞中的表达及调控。目标二： 使用我们独特人血管生成方法， 血管生成系统和基于CRISPR的技术。目的三是确定功能 lncEGFL 70 S在血管生成中的作用机制。

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.