Orphan Nuclear Receptor TR3 in tumor angiogenesis and associated microvessel perm

孤儿核受体 TR3 在肿瘤血管生成和相关微血管生成中的作用

基本信息

批准号：
7728627
负责人：
HUIYAN ZENG
金额：
$ 35.28万
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：
2009
资助国家：
美国
起止时间：
2009-07-07 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7728627
关键词：
Adherence Adherens Junction Adult Adverse effects Angiogenic Factor Antibodies Area Avastin Binding Sites Cell Proliferation Cells Colon Colon Carcinoma Complementary DNA Complex Data Defect Development Dominant-Negative Mutation Down-Regulation ETS1 gene Edema Effectiveness Endothelial Cells Endothelium Family member Figs - dietary Gases Goals Grant Growth Human In Vitro Intercellular Junctions Knockout Mice Length Lewis Lung Carcinoma Matrix Metalloproteinases Mediating Messenger RNA Molecular Mus NR4A1 gene Nucleic Acid Regulatory Sequences Pathologic Neovascularization Permeability Plasma Proteins Play Proliferating Protein Family Proteins Refuse Disposal Regulation Reporting Role Signal Transduction Solid Neoplasm Staging Testing Tetracyclines Therapeutic Tissues Toxic effect Transactivation Transcription Coactivator Transgenes Transgenic Mice Tumor Angiogenesis Vascular Endothelial Growth Factors Vascular Endothelium Vascular blood supply Wild Type Mouse Work adherent junction analog angiogenesis cadherin 5 cancer therapy cancer type density humanized antibody in vivo insight matrigel melanoma nutrition orphan nuclear receptor TR3 overexpression promoter public health relevance therapeutic target transcription factor transgene expression tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): In order to grow beyond minimal size (3 mm3), tumors must generate a new vascular supply (angiogenesis) for the purpose of gas exchange, cell nutrition, and waste disposal. Among many angiogenic factors, VEGF-A has been shown to be the most important one in tumor angiogenesis and associated microvessel permeability to plasma proteins. A humanized antibody to VEGF-A165, Avastin, has been developed and shown to be effective in treating several types of cancers. However, Avastin has significant toxic side effects. Therefore, it is desirable to identify whether downstream targets of VEGF signaling can be used as promising therapeutic targets with less toxic effects. Our recent work showed that the orphan nuclear receptor TR3 (mouse analogue, Nur77) was highly upregulated by VEGF-A165 in cultured endothelial cells and in pathological angiogenesis and that it was required for VEGF-A165-induced endothelial cell proliferation and survival in vitro and Matrigel angiogenesis in vivo. Overexpression of TR3 cDNA induced endothelial cell proliferation and survival in vitro and in Matrigel angiogenesis in vivo, even in the absence of VEGF-A165. The transcriptional activity of TR3 is required for its function in angiogenesis. Further, B16 melanoma growth was completely inhibited in Nur77-/- mice, most likely through inhibition of tumor angiogenesis. Nur77-/- mice have no obvious developmental defect. Our overall hypothesis is that TR3/Nur77 regulates tumor growth through regulation of angiogenesis and associated microvessel permeability. To prove our hypothesis and gain insight into the molecular mechanisms, we will study tumor growth in transgenic mice that Nur77 activity is inhibited in mouse endothelium in Aim 1. Our second aim will investigate that TR3/Nur77 regulates tumor angiogenesis and its associated microvessel permeability by destabilization of VE-cadherin adherences junctions. In the last aim, we will delineate the transcriptional mechanisms by which TR3 regulates VE-cadherin expression. The information from this study will not only enhance our understanding of the pathophyiosiology of tumorigenesis but also help us to develop effective therapeutic approaches for treatment of cancers. PUBLIC HEALTH RELEVANCE: The mechanism of tumor growth is largely unknown. Our current proposal will identify that Nur77 is an excellent target for cancer therapy.

描述（由申请人提供）：为了超过最小尺寸（3 mm3），肿瘤必须产生新的血管供应（血管生成），以实现气体交换，细胞营养和废物处理。在许多血管生成因子中，VEGF-A已被证明是肿瘤血管生成和相关的微血管渗透性对血浆蛋白的最重要的因素。已经开发出一种对VEGF-A165的人源化抗体，已开发并证明可以有效治疗几种类型的癌症。但是，阿瓦斯汀具有明显的毒性副作用。因此，希望确定VEGF信号的下游目标是否可以用作有前途的治疗靶标的毒性较少。我们最近的工作表明，在培养的内皮细胞和病理血管生成中，VEGF-A165高度上调了孤儿核受体TR3（小鼠类似物，NUR77），在VEGF-A165诱导的内皮细胞增殖和生存中，植物和伴随的植物生存是vEGF-A165所必需的。 TR3 cDNA的过表达在体外以及体内的基质凝胶血管生成中诱导的内皮细胞增殖和存活，即使在没有VEGF-A165的情况下也是如此。 TR3在血管生成中的功能是必需的。此外，在NUR77 - / - 小鼠中，B16黑色素瘤的生长完全受到抑制肿瘤血管生成。 NUR77 - / - 小鼠没有明显的发育缺陷。我们的总体假设是，TR3/NUR77通过调节血管生成和相关微血管通透性来调节肿瘤的生长。为了证明我们的假设并洞悉分子机制，我们将研究转基因小鼠的肿瘤生长，即AIM 1中的小鼠内皮中抑制NUR77活性。我们的第二个目标将调查TR3/NUR77调节肿瘤血管生成及其与ve-Cadherens of Ve-Cadherions de-Cadherensebensions gribensebense nerderense hearsherenserens nerderense nerderense nerderense nerderence nerderense nerderense nerherenserens nerherdensebensebensions nagctctctctctctctctctctctsctions in tr3/nur77。在最后一个目标中，我们将描述TR3调节VE-钙粘蛋白表达的转录机制。这项研究的信息不仅将增强我们对肿瘤发生病理生物生物学的理解，而且还可以帮助我们开发有效的治疗方法来治疗癌症。公共卫生相关性：肿瘤生长的机制在很大程度上尚不清楚。我们目前的建议将确定NUR77是癌症治疗的绝佳目标。