Targeting orphan nuclear receptor TR3/Nur77 for tumor angiogenesis

靶向孤儿核受体 TR3/Nur77 促进肿瘤血管生成

基本信息

批准号：
8956916
负责人：
HUIYAN ZENG
金额：
$ 8.7万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-07 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8956916
关键词：
Adenoviruses Adult Adverse effects Angiogenic Factor Antisense DNA Biological Assay Cell Proliferation Cells Chemicals Clinic Collaborations Colon Colorectal Cancer Colorectal Neoplasms DNA Binding Domain Data Defect Development Dominant-Negative Mutation EGF gene Endothelial Cells Endothelium Face Future Goals Histamine Homologous Gene Human In Vitro Institutes Knockout Mice Knowledge Lung Malignant Neoplasms Manuscripts Massachusetts Mission Molecular Mus NR4A1 gene Neoplasm Metastasis Neoplasms in Vascular Tissue Outcome Pathologic Neovascularization Peptides Permeability Phosphotransferases Physiologic Neovascularization Play Preparation Public Health Research Resistance Role Sepsis Serotonin Signal Pathway Skin Small Interfering RNA Solid Neoplasm Stream System Technology Testing Therapeutic Tissues Transactivation Transgenic Mice Translations Tube Tumor Angiogenesis Tumor Necrosis Factor-alpha Up-Regulation Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Wild Type Mouse Wound Healing analog angiogenesis base bevacizumab cancer therapy disability drug use screening improved in vivo inhibitor/antagonist kinase inhibitor matrigel medical schools migration mutant nanoparticle neoplastic cell neutralizing antibody novel orphan nuclear receptor TR3 overexpression public health relevance receptor response small hairpin RNA small molecule targeted treatment therapeutic angiogenesis transcription factor tumor tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): Angiogenesis is critical for solid tumor growth beyond minimal size. We have demonstrated that orphan nuclear receptor TR3 (mouse homolog Nur77) transcription factor plays critical roles in tumor angiogenesis. Tumor growth and angiogenesis induced by VEGF-A, histamine and serotonin are almost completely inhibited in Nur77 knockout mice. However, Nur77 null mice are viable, fertile, develop an apparently normal adult vasculature and have no defect in normal skin wound healing. Together these findings suggest that TR3/Nur77 is required for pathological angiogenesis, but not for developmental or physiological angiogenesis, and render it a potentially useful target for anti-angiogenic therapy. We also found that retroviruse expressing TR3/Nur77 siRNA almost completely inhibits the angiogenesis induced by VEGF-A in a Matrigel angiogenesis assay in vivo. In the present proposal, we will identify biomolecules that target TR3/Nur77 to inhibit tumor growth and metastasis. In specific Aim, we will determine whether tumor growth and metastasis can be inhibited by targeting TR3/Nur77. This research will identify siRNA and peptides that could have potential in anti-angiogenic therapy for cancer, providing evidence that a transcription factor can be targetable. This application has translation potential.

描述（由适用提供）：血管生成对于超出最小尺寸的实体瘤生长至关重要。我们已经证明了孤儿核受体TR3（小鼠同源性NUR77）转录因子在肿瘤血管生成中起关键作用。 VEGF-A，组胺和5-羟色胺诱导的肿瘤生长和血管生成在NUR77敲除小鼠中几乎完全抑制。但是，NUR77无效小鼠是可行的，肥沃的，发展出明显正常的成年血管，并且在正常皮肤伤口愈合中没有缺陷。这些发现一起表明，TR3/NUR77是病理血管生成所必需的，而不是发育或物理血管生成，并且使其成为抗血管生成疗法的潜在有用靶标。我们还发现，表达TR3/NUR77 siRNA的逆转录病毒几乎完全抑制了在体内的Matrigel血管生成测定中VEGF-A诱导的血管生成。在本提案中，我们将确定靶向TR3/NUR77以抑制肿瘤生长和转移的生物分子。在特定目标中，我们将通过靶向TR3/NUR77来确定肿瘤生长和转移是否可以抑制。这项研究将确定可能在抗癌症抗血管生成治疗中具有潜力的siRNA和PETIDE，提供证据表明转录因子可以是目标。该应用具有翻译潜力。