Orphan nuclear receptor Nur77 and intestinal inflammmation

孤儿核受体 Nur77 与肠道炎症

基本信息

批准号：
7588322
负责人：
DEZHENG ZHAO
金额：
$ 25.5万
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：
2009-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7588322
关键词：
Acute Adhesions Animal Model Attenuated Blood Circulation Cell Proliferation Cells Chronic Colitis Dominant-Negative Mutation Endothelial Cells Endothelium Epithelial Cell Proliferation Feasibility Studies Functional disorder Gene Expression Genes Genetic Transcription Genus Cola Histamine Human IL8 gene Immune Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Interleukin-10 Intestinal Mucosa Intestines Knockout Mice Leukocytes Measures Messenger RNA Methods Microvascular Permeability Molecular Mucous Membrane Mus Nuclear Orphan Receptor Nutrient Outcome Patients Permeability Phase Pilot Projects Play Process Proteins Resolution Role Severities Signal Transduction Staging Sulfonic Acids System Techniques Testing Tissues Transfection Transgenes Transgenic Mice Tumor Necrosis Factor-alpha Tumor Necrosis Factors Vascular Endothelial Growth Factors Vascular Permeabilities Western Blotting Wound Healing angiogenesis cell type in vivo insight killings migration novel pathogen public health relevance receptor repaired research study

项目摘要

DESCRIPTION (provided by applicant): Intestinal inflammation involves two stages: early inflammatory phase and later resolution phase. The early phase is characterized by pathogen-induced activation of various cell types and release of numerous inflammatory mediators which then cause infiltration of leukocytes from circulation into intestinal mucosa to kill pathogens. The process also inevitably causes intestinal mucosal damage. The later phase involves proliferation of epithelial cells to repair damaged tissue. Activation and dysfunction of Intestinal microvascular endothelial cells (IMEC) during the early phase causes increased adhesion and transmigration of circulating immune cells into the mucosa. New microvessel formation (angiogenesis) which is induced by inflammatory mediators presumably has dual roles: one to increase leukocyte infiltration in the early phase and another to provide nutrients for extensive intestinal epithelial cell proliferation and tissue repair in the late phase. However, the exact functions and molecular mechanisms of IMEC in these processes are largely unknown. In addition to tumor necrosis factor-1 (TNF1), vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) and histamine are two potent microvascular permeability factors that are involved in dysfunction of microvascular endothelium. In order to profile the gene expression induced by VEGF/VPF we found that orphan nuclear receptors including Nur77, Nurr1 and Nor1 were highly induced. However nothing is known as to whether these orphan nuclear receptors play a role in intestinal inflammation though it can be induced by numerous factors such as TNF1 and LPS. In this pilot feasibility study we will focus on expression and function of Nur77 during colitis. Our preliminary results support the relevance of Nur77 in colitis. Therefore, our overall hypothesis of this proposal is that one important mechanism by which Nur77 modulates colitis is to regulate the functions of intestinal microvascular endothelium. To test our hypothesis, we will characterize the expression of Nur77 in animal models of colitis and determine whether Nur77 is involved in the formation of acute and chronic colitis. Our study will provide important insights on the role and mechanisms of novel orphan nuclear receptor Nur77 in inflammatory responses including human colitis. PUBLIC HEALTH RELEVANCE: The pathophysiology of inflammatory bowel diseases is largely unknown. Our preliminary study suggests that novel orphan nuclear receptor Nur77 is involved in intestinal inflammation. We will further investigate the exact functions and mechanisms of this gene in both acute and chronic colitis.

描述（由申请人提供）：肠道炎症涉及两个阶段：早期炎症阶段和后来的分辨率阶段。早期阶段的特征是病原体引起的各种细胞类型的激活以及众多炎症介质的释放，从而导致白细胞从循环中浸润到肠粘膜中以杀死病原体。该过程不可避免地会造成肠粘膜损伤。后期涉及上皮细胞的增殖以修复受损的组织。早期肠道微血管内皮细胞（IMEC）的激活和功能障碍会导致循环免疫细胞的粘附和迁移增加到粘膜中。由炎症介质诱导的新微血管形成（血管生成）大概具有双重作用：一种是在早期增加白细胞浸润，另一种是为广泛的肠上皮细胞增殖和后期的组织提供营养。但是，在这些过程中，IMEC的确切功能和分子机制在很大程度上尚不清楚。除了肿瘤坏死因子1（TNF1）外，血管内皮生长因子/血管通透性因子（VEGF/VPF）和组胺是两个有效的微血管渗透因子，这些微血管渗透率因子涉及微血管内皮的功能障碍。为了介绍VEGF/VPF诱导的基因表达，我们发现包括NUR77，Nurr1和Nor1在内的孤儿核受体被高度诱导。然而，这些孤儿核受体是否在肠道炎症中发挥作用，尽管它可以由TNF1和LPS等许多因素引起，但尚无众所周知。在这项试验性可行性研究中，我们将重点关注结肠炎期间NUR77的表达和功能。我们的初步结果支持NUR77在结肠炎中的相关性。因此，我们对该提案的总体假设是，NUR77调节结肠炎的一种重要机制是调节肠道微血管内皮的功能。为了检验我们的假设，我们将表征在结肠炎动物模型中NUR77的表达，并确定Nur77是否参与急性和慢性结肠炎的形成。我们的研究将提供有关新型孤儿核受体NUR77在包括人类结肠炎在内的炎症反应中的作用和机制的重要见解。公共卫生相关性：炎症性肠病的病理生理学在很大程度上是未知的。我们的初步研究表明，新型的孤儿核受体NUR77参与肠炎。我们将进一步研究该基因在急性和慢性结肠炎中的确切功能和机制。