REGULATION OF VEGF MRNA STABILITY BY HYPOXIA

缺氧对 VEGF mRNA 稳定性的调节

• 批准号: 6343591
• 负责人: HENRY M FURNEAUX
• 金额: $ 30.74万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6343591
• 关键词: angiogenesis; gene expression; genetic regulation; genetic regulatory element; hypoxia; messenger RNA; molecular cloning; protein structure; transcription factor; vascular endothelial growth factors

DESCRIPTION (Adapted from Investigator's Abstract): Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis in diabetic retinopathy, cancer and coronary heart disease. The expression of VEGF is tightly controlled to the cellular oxygen tension. Previous studies have shown that VEGF mRNA is markedly stabilized under hypoxic conditions. The molecular mechanisms underlying the regulation of VEGF mRNA stability are not well understood. In the preliminary results the applicant showed that the stability of VEGF mRNA is controlled by a cis acting element in its 3'UTR. They have also identified a trans acting factor (HuR) that binds to this element and increases the expression of VEGF. In addition, they show that HuR itself is regulated by hypoxia. This proposal will focus on the role of HuR in hypoxic regulation of VEGF mRNA stability. The proposed studies may be important since they could lead to the generation of new drugs that will regulate VEGF expression at the post transcriptional level. The specific aims of the proposal are the following: (1) To determine the fine structure of the HuR/VEGF mRNA complex. To generate mutations in both the mRNA element and HuR and determine their effect on VEGF expression; (2) To design selective inhibitors of HuR/VEGF mRNA complexes; (3) To identify and clone HuR associate proteins that modify its activity; (4) To determine how hypoxia regulates HuR expression; and (5) To determine how HuR stabilizes VEGF mRNA.

描述（改编自研究者摘要）： 血管内皮生长因子（VEGF）是血管生成的重要介质 糖尿病视网膜病变、癌症和冠心病中的血管生成。 VEGF 的表达受到细胞氧的严格控制 紧张。先前的研究表明 VEGF mRNA 显着 缺氧条件下稳定。潜在的分子机制 VEGF mRNA 稳定性的调节尚不清楚。在 申请人初步结果表明VEGF mRNA的稳定性 由其 3'UTR 中的顺式作用元件控制。他们还有 鉴定出与该元件结合的反式作用因子 (HuR)，并且 增加 VEGF 的表达。此外，他们还表明 HuR 本身 受缺氧调节。该提案将重点关注 HuR 在 缺氧调节 VEGF mRNA 稳定性。拟议的研究可能是 很重要，因为它们可能会导致新药的产生 在转录后水平调节 VEGF 表达。具体的 该提案的目的如下： (1) 确定罚款 HuR/VEGF mRNA 复合物的结构。在两者中产生突变 mRNA元件和HuR并确定它们对VEGF表达的影响； (2)设计HuR/VEGF mRNA复合物的选择性抑制剂； (3) 至 鉴定并克隆可改变其活性的 HuR 相关蛋白； (4) 确定缺氧如何调节 HuR 表达； (5) 确定 HuR 如何稳定 VEGF mRNA。