Macrophage Gene Expression in Mucosal Inflammation

粘膜炎症中的巨噬细胞基因表达

基本信息

批准号：
7859122
负责人：
SCOTT E PLEVY
金额：
$ 1.8万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2009-07-17 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7859122
关键词：
1-Phosphatidylinositol 3-Kinase Anti-Inflammatory Agents Anti-inflammatory Antibodies Area Attenuated Be++ element Beryllium Biliverdine Carbon Monoxide Catalytic Domain Cells Chronic Colitis Crohn&apos s disease DNA Binding Data Disease Enterocolitis Environmental Risk Factor Event Experimental Models Family Fc Receptor Gastrointestinal tract structure Gene Expression Genetic Transcription Goals Heme Histologic Human IFN consensus sequence binding protein IL9 gene Immune Immune system Immunologics Indium Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Interferons Interleukin-10 Interleukin-12 Interleukin-9 Intestines Kinetics Lead Ligation Macrophage Activation Mediating Modeling Molecular Mucositis Mus Mutant Strains Mice Nucleosomes Pathogenesis Pathway interactions Process Production Proteins Reagent Regulation Regulatory Element Research Personnel Resistance Role Signal Transduction Signal Transduction Pathway Stimulus Testing Therapeutic Effect Therapeutic Intervention Time Transgenic Mice Work cytokine heme oxygenase-1 in vivo insight mRNA Expression macrophage member mouse model mutant novel novel therapeutic intervention novel therapeutics nuclear factors of activated T-cells overexpression promoter protective effect protein protein interaction research study response transcription factor

项目摘要

Experiments proposed in this application will explore the role of macrophage activation in the pathogenesis of the inflammatory bowel diseases (IBD). We will focus on the molecular regulation of IL-12 p40 in macrophages as one of the most biologically significant events in T-helper1 (Th1)-mediated chronic inflammation. We have recently described a novel composite element in the IL-12 p40 promoter that interacts with members of the nuclear factor of activated T cells (NFAT) and interferon regulatory factor (IRF) families of transcription factors. This control element is involved in the synergistic induction of IL-12 p40 promoter activity by bacterial products and interferon-y (IFN-y), and is an important target for inhibition of IL- 12 p40 gene expression through several signal transduction pathways. The overall goal of this proposal is to understand the molecular regulation of IL-12 p40 in experimental models of IBD. Experiments will elucidate the role of two newly appreciated anti-inflammatory signal transduction pathways in macrophages: Heme oxygenase-1 (HO-1) and phosphatidylinositol-3-kinase (PI3K). We hypothesize that these anti-inflammatory pathways converge through regulation of NFAT/IRF interactions at the IL-12 p40 promoter. By inhibiting IL-12 p40, HO-1 and PI3K serve as molecular "brakes" for macrophage activation that may limit the extent and duration of chronic intestinal inflammation. lnterleukin-12 (IL-12) is an inflammatory protein that has been demonstrated to be important in the progression of human Crohn's disease (CD). In this application, we will test therapeutic interventions in mouse models of CD to inhibit IL-12 production by cells of the immune system called macrophages. Studies in this application will give us important information about immune inhibitory pathways that may be defective in human IBD and may lead to new therapeutic interventions in human IBD that target macrophages and IL- 12.

本应用中提出的实验将探讨巨噬细胞激活在发病机理中的作用炎症性肠病（IBD）。我们将重点介绍IL-12 p40的分子调节巨噬细胞是T-Helper1（TH1）介导的慢性慢性事件中最重要的事件之一炎。我们最近描述了IL-12 p40启动子中一种新型的复合元素与活化T细胞（NFAT）和干扰素调节因子（IRF）的核因子成员相互作用转录因子家族。该控制元素参与IL-12 p40的协同诱导细菌产物和干扰素-Y（IFN-Y）的启动子活性，是抑制IL-的重要靶标通过几种信号转导途径的12个P40基因表达。该提案的总体目标是了解实验中IL-12 p40的分子调节 IBD的模型。实验将阐明两个新欣赏的抗炎信号的作用巨噬细胞中的转导途径：血红素加氧酶-1（HO-1）和磷脂酰肌醇-3-激酶（PI3K）。我们假设这些抗炎途径通过调节NFAT/IRF汇聚 IL-12 p40启动子的相互作用。通过抑制IL-12 p40，HO-1和PI3K用作分子“制动器” 对于可能限制慢性肠炎的程度和持续时间的巨噬细胞激活。 lnterleukin-12（IL-12）是一种炎症蛋白，已证明在人类克罗恩病的进展（CD）。在此应用中，我们将测试 CD的小鼠模型可抑制称为巨噬细胞的免疫系统细胞产生的IL-12。研究在此应用中，我们将为我们提供有关免疫抑制途径的重要信息，这些途径可能有缺陷在人类IBD中，可能导致针对巨噬细胞和IL-的人类IBD的新治疗干预措施 12。