Expression and Function of TR3/nur77 in angiogenesis

描述（由申请人提供）： 病理性血管生成是癌症和各种缺血性和炎性疾病的标志。 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不仅参与血管生成的几个步骤，而且是迄今为止鉴定的使微血管对循环大分子高渗透性的唯一有效因子。 VPF/VEGF广泛重新编程基因表达，刺激内皮细胞迁移和分裂，保护内皮细胞免受凋亡和衰老。 为了分析VPF/VEGF诱导的基因，使用从VPF/VEGF刺激的培养HUVEC中获得的RNA进行DNA微阵列分析。 核受体TR 3是一种转录因子，是高度上调的基因之一。 此外，TR 3的小鼠同源物Nur 77在VPF/VEGF处理的小鼠的肠系膜中上调，其中仅EC表达VPF/VEGF受体。 进一步的实验表明TR 3是VPF/VEGF刺激HUVEC增殖所必需的。 然而，正义TR 3的过表达抑制VPF/VEGF刺激的HUVEC迁移，但是通过反义方法阻断内源性TR 3的表达在VPF/VEGF不存在的情况下触发HUVEC迁移。 已知TR 3/nur 77在发育、稳态和疾病中起关键作用。 然而，TR 3/nur 77是否在血管生成中起作用尚不清楚。 本申请的总体目标是研究核受体TR 3/nur 77在VPF/VEGF诱导的血管生成中的功能以及调节VPF/VEGF诱导的TR 3表达的信号通路。 本申请的具体目的是：（1）研究TR 3/nur 77在VPF/VEGF诱导的病理性血管生成、肿瘤和创伤中的表达。 (2)确定TR 3/nur 77在血管生成中的功能。 (3)定义调节TR 3/Nur 77表达的分子机制。

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.