REGULATION OF VEGF MRNA STABILITY BY HYPOXIA

描述（改编自研究者摘要）： 血管内皮生长因子（VEGF）是一种重要的介导因子， 糖尿病视网膜病变、癌症和冠心病中的血管生成。 VEGF的表达受细胞氧浓度的严格控制 张力以往的研究表明，VEGF mRNA的表达与肿瘤的生长密切相关。 在低氧条件下稳定。的分子机制 VEGF mRNA稳定性的调节还不清楚。在 申请人的初步结果表明，VEGF mRNA的稳定性 由其3 'UTR中的顺式作用元件控制。他们还 鉴定了与该元件结合的反式作用因子（HuR）， 增加VEGF的表达。此外，他们还表明，HuR本身 是由缺氧调节的该提案将侧重于人权维护者在以下方面的作用： 低氧对VEGF mRNA稳定性的调节。拟议的研究可能是 这很重要，因为它们可能导致产生新的药物， 在转录后水平调节VEGF的表达。具体 建议的目的如下：（1）确定罚款 HuR/VEGF mRNA复合物的结构。在这两种基因中产生突变 mRNA元件和HuR，并测定它们对VEGF表达的影响; (2)设计选择性HuR/VEGFmRNA复合物抑制剂; 鉴定和克隆修饰其活性HuR相关蛋白;（4） 确定缺氧如何调节HuR表达;和（5）确定 HuR如何稳定VEGF mRNA。

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.