Role of long noncoding RNAs in human ocular angiogenesis

长链非编码RNA在人眼血管生成中的作用

• 批准号: 9330862
• 负责人: Shusheng Wang
• 金额: $ 37.63万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330862
• 关键词: Age related macular degeneration; Angiogenesis Inhibitors; Animals; Antibodies; Biological Process; Blood Vessels; CRISPR/Cas technology; Cell Cycle Regulation; Choroid; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Development; Disease; Endothelial Cells; Enhancers; FDA approved; Genes; Genetic Transcription; Genomic Imprinting; Goals; Homeostasis; Human; In Vitro; Investigation; Laboratories; Light; MAP Kinase Gene; MAX gene; Modeling; Nature; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Primates; Proto-Oncogene Proteins c-akt; Recruitment Activity; Regulation; Research; Role; System; Technology; Testing; Therapeutic; Tissues; Transcript; Translating; Treatment Factor; Untranslated RNA; Vascular Diseases; Vascular Endothelial Growth Factors; Work; angiogenesis; base; cancer therapy; combat; genome-wide; human tissue; in vivo; insight; new therapeutic target; novel; ocular angiogenesis; promoter; protein function; transcription factor

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.

该项目致力于阐明长链非编码RNA的功能和机制 （lncRNA）在人眼血管生成中的作用。使用血管抗体进行抗血管生成治疗 内皮生长因子（VEGF）已被 FDA 批准用于癌症治疗，并且 湿性年龄相关性黄斑变性 (AMD) 的首选治疗方法。然而，在许多 病例中，抗血管生成治疗的疗效仍然有限，部分患者未能缓解 进行抗VEGF治疗。血管生成的彻底机制研究，特别是在 人类有必要开发新颖的替代治疗方法。长- 我实验室的长期目标是破译非编码 RNA 在眼血管中的作用机制 发育和疾病。 LncRNA 代表一大群长（通常 >200nt）非编码 RNA具有多种生物学功能，但它们在血管生成中的作用仍不清楚。我们的 全基因组搜索已鉴定出一组富含人类内皮细胞 (EC) 的 lncRNA。 该提案重点关注一种新型灵长类特异性、富含 EC 的 lncRNA lncEGFL7OS，它是 位于EGFL7/miR-126基因的反义链中。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 lncEGFL7OS 的组织假设 通过调节 EGFL7/miR- 的转录活性来调节人类眼部血管生成所需的 126. 目标 I 是检查 EC 中 lncEGFL7OS 的表达和调节。目标二是 利用我们独特的人类技术确定 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 III 是确定函数 lncEGFL7OS在血管生成中的机制。