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

基本信息

批准号：
9762935
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
项目类别：
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/9762935
关键词：
Age related macular degeneration Angiogenesis Inhibitors Animals Antibodies Biological Process Blood Vessels CRISPR/Cas technology Cell Cycle Regulation Choroid 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 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 recruit transcription factor

项目摘要

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.

该项目的重点是阐明长未编码RNA的功能和机制（LNCRNA）在人眼血管生成中。抗血管生成疗法使用抗血管的抗体 FDA已批准内皮生长因子（VEGF）进行癌症治疗，也是与湿年龄相关的黄斑变性（AMD）的第一个治疗方法。但是，许多人病例，抗血管生成疗法的功效仍然有限，有些患者未能做出反应进行抗VEGF治疗。对血管生成的彻底机械研究，尤其是在为了开发新颖和替代性的治疗方法，应要求人类。长期我的实验室的术语目标是破译眼睛血管中未编码RNA的机制发展与疾病。 lncRNA代表一大批长（通常> 200nt）非编码具有不同生物学功能的RNA，其在血管生成中的作用仍然在很大程度上不清楚。我们的全基因组搜索已经确定了一组人内皮细胞（EC）富集的LNCRNA。该提案重点是一种新颖的灵长类动物特异性，富含EC的Lncrna lncegfl7os 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，需要人类的眼血管生成 126。目的I是检查EC中LNCEGFL7OS的表达和调节。 AIM II是使用我们的独特人血管生成系统和基于CRISPR的技术。 AIM III是确定功能 LNCEGFL7OS在血管生成中的机制。