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：
7116688
负责人：
SCOTT E PLEVY
金额：
$ 6.76万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2006-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7116688
关键词：
antigen presenting cell bacterial antigens cellular immunity enteric bacteria gene expression inflammation interleukin 12 macrophage mixed tissue /cell culture mucosa tissue /cell culture transcription factor

项目摘要

EXCEED THE SPACE PROVIDED. 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 (Thl)-mediated chronic inflammation. We have recently described a novel composite element in the IL-12p40 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. PERFORMANCE SITE ========================================Section End===========================================

超过提供的空间。本应用中提出的实验将探讨巨噬细胞激活在炎症性肠病（IBD）的发病机理中的作用。我们将重点介绍巨噬细胞中IL-12 p40的分子调节，这是T-Helper1（THL）介导的慢性炎症中最重要的事件之一。我们最近描述了IL-12P40启动子中的一种新型复合元件，该元素与转录因子的活化T细胞（NFAT）和干扰素调节因子（IRF）家族的核因子成员相互作用。该控制元素参与了通过细菌产物和干扰素-Y（IFN-Y）对IL-12 p40启动子活性的协同诱导，并且是通过几种信号转导途径抑制IL-12 p40基因表达的重要靶标。该提案的总体目标是了解IBD实验模型中IL-12 p40的分子调节。实验将阐明巨噬细胞中两种新认识的抗炎信号转导途径的作用：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IL-12 p40启动子的NFAT/IRF相互作用来融合。通过抑制IL-12 p40，HO-1和PI3K用作巨噬细胞激活的分子“制动器”，这可能会限制慢性肠炎的程度和持续时间。表演站点=============================================================================================