Role of long noncoding RNAs in human ocular angiogenesis

本项目致力于阐明长非编码RNA的功能和机制 (LncRNAs)在人眼血管生成中的作用。使用抗血管抗体的抗血管生成治疗 血管内皮生长因子(VEGF)已被FDA批准用于癌症治疗，并 湿性老年性黄斑变性(AMD)的首选治疗方案。然而，在许多情况下 5例中，抗血管生成治疗的疗效仍然有限，一些患者没有反应 以抗血管内皮生长因子治疗为主。血管生成的深入机制研究，特别是在 为了开发新的和可替代的治疗方法，人类是有必要的。长的- 我的实验室的学期目标是破译眼血管中非编码RNA的机制 发展和疾病。LncRNA代表一大组长的(通常为&gt；200nt)非编码 具有不同生物学功能的RNA，它们在血管生成中的作用在很大程度上仍不清楚。我们的 全基因组搜索发现了一组富含人内皮细胞(EC)的lncRNAs。 这项建议关注的是一种新的灵长类特异的、富含EC的lncRNA lncEGFL7OS，它是 定位于EGFL7/miR-126基因的反义链上。根据我们的初步数据和 我们最近开发了一个独特的系统，我们测试了lncEGFL7OS是 通过调节EGFL7/miR的转录活性对人类眼血管生成所必需的 126.目的研究血管内皮细胞中lncEGFL7OS的表达及调控。目标二是 利用我们独一无二的人建立lncEGFL7OS在人眼血管生成中的关键作用 血管生成系统和基于CRISPR的技术。目标三是确定功能 LncEGFL7OS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.