Expression and Function of TR3/nur77 in angiogenesis

TR3/nur77在血管生成中的表达和功能

• 批准号: 6919216
• 负责人: HUIYAN ZENG
• 金额: $ 13.44万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-22 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919216
• 关键词: angiogenesis; biological signal transduction; cell migration; cell proliferation; cytoprotection; gene expression; genetically modified animals; growth factor receptors; laboratory mouse; microarray technology; neoplasm /cancer blood supply; nuclear receptors; pathologic process; receptor expression; tissue /cell culture; transcription factor; vascular endothelial growth factors; vascular endothelium permeability; wound

DESCRIPTION (provided by applicant): Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases. VPF/VEGF is the most important angiogenic factor because of its potency and selectivity for vascular endothelium. VPF/VEGF is not only involved in several steps of angiogenesis, but also the only potent factor rendering microvessels hyperpermeable to circulating macromolecules identified so far. VPF/VEGF extensively reprograms gene expression, stimulates endothelial cell migration and division, and protects endothelial cells from apoptosis and senescence. In order to profile the genes induced by VPF/VEGF, DNA microarray assay was conducted with RNA obtained from cultured HUVEC stimulated with VPF/VEGF. Nuclear receptor TR3, a transcription factor, is one of the highly upregulated genes. In addition, Nur77, the mouse homologue of TR3, is upregulated in the mesentery of VPF/VEGF-treated mouse, where only EC express VPF/VEGF receptors. Further experiments indicated that TR3 is required for VPF/VEGF-stimulated HUVEC proliferation. However, overexpression of sense TR3 inhibits VPF/VEGF-stimulated HUVEC migration, but blocking the expression of the endogenous TR3 by an antisense approach triggers HUVEC migration in the absence of VPF/VEGF. It is known that TR3/nur77 plays crucial roles in development, homeostasis and diseases. However, whether TR3/nur77 plays a role in angiogenesis is not known. The overall goal of this application is to study the function of the nuclear receptor TR3/nur77 in VPF/VEGF-induced angiogenesis and the signaling pathways that regulate VPF/VEGF-induced TR3 expression. The specific aims of this application are: (1) Investigate TR3/nur77 expression in the pathological angiogenesis induced by VPF/VEGF, tumors and wounding. (2) Determine the function of TR3/nur77 in angiogenesis. (3) Define the molecular mechanisms regulating TR3/Nur77 expression.

描述（由申请人提供）：病理血管生成是癌症以及各种缺血性和炎症性疾病的标志。 VPF/VEGF是最重要的血管生成因子，因为其对血管内皮的效力和选择性。 VPF/VEGF不仅参与了几个血管生成步骤，而且还参与了唯一的有效因子，使微血管与迄今为止确定的循环大分子高度渗透相关。 VPF/VEGF广泛重新编程基因表达，刺激内皮细胞迁移和分裂，并保护内皮细胞免受细胞凋亡和衰老的影响。 为了谱图由VPF/VEGF诱导的基因，使用从用VPF/VEGF刺激的HUVEC获得的RNA进行DNA微阵列测定。 核受体TR3是转录因子，是高度上调的基因之一。 此外，TR3的小鼠同源物NUR77在VPF/VEGF处理的小鼠的肠系膜中被上调，其中仅EC表达VPF/VEGF受体。 进一步的实验表明，VPF/VEGF刺激的HUVEC增殖需要TR3。 然而，感觉TR3的过表达抑制了VPF/VEGF刺激的HUVEC迁移，但在没有VPF/VEGF的情况下，通过反义方法阻止内源性TR3的表达触发HUVEC迁移。 众所周知，TR3/NUR77在发展，体内平衡和疾病中扮演着重要角色。 但是，尚不清楚TR3/NUR77在血管生成中是否起作用。 该应用的总体目标是研究VPF/VEGF诱导的血管生成中核受体TR3/NUR77的功能，以及调节VPF/VEGF诱导的TR3表达的信号传导途径。 该应用的具体目的是：（1）研究VPF/VEGF，肿瘤和伤口引起的病理血管生成中TR3/NUR77的表达。 （2）确定TR3/NUR77在血管生成中的功能。 （3）定义调节TR3/NUR77表达的分子机制。