Regulation of colitis by orphan nuclear receptor Nur77

孤儿核受体 Nur77 对结肠炎的调节

• 批准号: 8579528
• 负责人: DEZHENG ZHAO
• 金额: $ 37.85万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579528
• 关键词: Acute; Adherens Junction; Adhesions; Angiogenesis Inhibition; Apoptosis; Attenuated; Binding; Biological Process; Biopsy; Blocking Antibodies; Blood Vessels; Body Weight Changes; Cell Adhesion Molecules; Cell-Cell Adhesion; Cells; Chronic; Clinical; Colitis; Crohn' s disease; DNA Binding Domain; Development; Disease; Disease Progression; Dominant-Negative Mutation; Down-Regulation; Endothelial Cells; Endothelium; Enteral; Epithelial Cells; Fibroblasts; Functional disorder; Generations; Generic Drugs; Genes; Genetic; Goals; Healed; Human; Immune; Infiltration; Inflammation; Inflammation Mediators; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Integrins; Interleukin-10; Intestines; Lead; Leukocytes; Link; Luciferases; Measures; Mediating; Messenger RNA; MicroRNAs; Microvascular Permeability; Modeling; Molecular; Mucous Membrane; Mus; Mutant Strains Mice; Neurons; Nuclear Orphan Receptor; Nutrient; Pathogenesis; Patients; Permeability; Phenotype; Play; Publishing; Regulation; Reporter; Resolution; Role; Sampling; Signal Transduction; Sodium Dextran Sulfate; Structure; Sulfonic Acids; System; T-Lymphocyte; Testing; Tetanus Helper Peptide; Tissues; Transgenes; Transgenic Mice; Ulcerative Colitis; Vascular Endothelial Growth Factors; Vascular Permeabilities; adherent junction; angiogenesis; base; cadherin 5; cell growth; cell type; colon carcinogenesis; cytokine; feeding; healing; indexing; migration; mouse model; mutant; novel; novel therapeutics; pathogen; public health relevance; therapeutic target; tissue regeneration; tissue repair; transgene expression

DESCRIPTION (provided by applicant): The pathophysiology of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, has been studied extensively but. Disease mechanisms involve cross-talk amongst pathogens and various host cell types (luminal epithelial cells, enteric nerve cells, resident immune cells, fibroblasts, microvascular endothelia cells and circulating leukocytes, inter alia). Amongst these, intestinal microvascular endothelial cells (IMEC) may play a central role in the progression of the disease by modulating infiltration of circulating immune cells and providing nutrients for inflammation resolution and tissue repair. Activated IMEC secrete various pro- inflammatory mediators and express cell-cell adhesion molecules that facilitate leukocyte infiltration. In addition, increased microvessel formation (angiogenesis) during colitis could promote inflammation and impact tissue regeneration/healing. Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) has been shown to play important roles in experimental colitis. In our initial efforts to profile VEGF/VPF-induced genes in cultured human endothelial cells HUVEC, we found that the orphan nuclear receptor Nur77 was highly induced in these cells. Nur77 has been shown to play important roles in cell growth, differentiation and apoptosis. The goal of this application isto test the hypothesis that Nur77 modulates colitis by regulating the functions of intestinal microvascular endothelium: such as microvessel permeability, angiogenesis and leukocyte transendothelial migration. To this end, we have shown that Nur77 is highly induced in acute trisnitrobenzene sulfonic acid (TNBS) and dextran sulfate sodium (DSS) experimental colitis. Further, high levels of Nur77 are present in the colons of patients with IBD, when compared to non-inflamed colonic tissues. The present application will investigate how Nur77 specifically regulates endothelial functions and impacts progression of colitis. We propose that Nur77 expression in IMEC and infiltrating immune cells might play an important role in regulating acute intestinal inflammation. Aim 1 will examine several models of colitis in mice express Nur77 exclusively in endothelial cells. Aim 2 will determine the role of VE-cadherin-based adherens junction in colitis. Aim 3 will dissect out regulatory mechanisms of VE-cadherin expression by Nur77. Several genetic approaches include generation of inducible endothelial specific transgenic mice to express wild-type Nur77 and dominant negative Nur77 on both wild-type and Nur77-null backgrounds. Our studies have high impact by linking Nur77 to IBD pathogenesis and indicate vascular components of inflammation that could serve as therapeutic targets.

描述（由申请人提供）：炎症性肠病（IBD），克罗恩病和溃疡性结肠炎的病理生理学已经进行了广泛的研究。疾病机制涉及病原体和各种宿主细胞类型（腔上皮细胞，肠神经细胞，常驻免疫细胞，成纤维细胞，微血管内皮细胞和循环白细胞，Interione）的串扰。其中，肠道微血管内皮细胞（IMEC）可能通过调节循环免疫细胞的浸润并为炎症分辨率和组织修复提供营养，在疾病的进展中起核心作用。激活的IMEC分泌各种促炎性介质和促进白细胞浸润的表达细胞粘附分子。此外，结肠炎过程中的微血管形成（血管生成）增加可以促进炎症并影响组织再生/愈合。血管内皮生长因子/血管通透性因子（VEGF/VPF）已显示在实验性结肠炎中起重要作用。在我们最初在培养的人内皮细胞中介绍VEGF/VPF诱导的基因的努力中，我们发现在这些细胞中孤立的核受体NUR77高度诱导。 NUR77已显示在细胞生长，分化和凋亡中起重要作用。该应用的目的是测试NUR77通过调节肠道微血管内皮功能调节结肠炎的假设：例如微血管通透性，血管生成和白细胞跨内皮细胞迁移。为此，我们已经表明，NUR77在急性三硝基苯磺酸（TNB）和硫酸葡萄糖硫酸钠（DSS）实验性结肠炎中高度诱导。此外，与非炎症的结肠组织相比，IBD患者的结肠中存在高水平的NUR77。本应用将调查NUR77如何专门调节内皮功能并影响结肠炎的进展。我们建议在IMEC和浸润的免疫细胞中的NUR77表达可能在调节急性肠道炎症中起重要作用。 AIM 1将检查仅在内皮细胞中仅表达NUR77的小鼠结肠炎模型。 AIM 2将确定基于VE-钙粘蛋白的粘附在结肠炎中的作用。 AIM 3将通过NUR77剖析VE-钙粘蛋白表达的调节机制。几种遗传方法包括生成诱导的内皮特异性转基因小鼠，以在野生型和NUR77-NULL背景上表达野生型NUR77和显性负NUR77。我们的研究通过将NUR77与IBD发病机理联系起来，并表明炎症的血管成分具有很大的影响，该血管成分可以用作治疗靶点。