Toll-like receptors and intestinal inflammation

Toll 样受体与肠道炎症

• 批准号: 7617102
• 负责人: CHARALABOS POTHOULAKIS
• 金额: $ 27.84万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617102
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adenocarcinoma Cell; Animal Experiments; Apical; Bacteria; Binding; CCL20 gene; Cell Line; Cells; Characteristics; Chemotactic Factors; Chronic; Clinical; Clostridium difficile tcdA protein; Colitis; Collection; Colon; Colon Adenocarcinoma; Cytokine Gene; DUSP1 gene; Development; Epithelial; Epithelial Cells; Epithelium; Family; Flagellin; Functional disorder; Gene Expression; Genus Cola; Goals; Human; IL8 gene; Immune response; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Injury; Interleukin-10; Intestines; Intracolonic; Invaded; Knockout Mice; Ligands; Lipoproteins; Listeria; MEKs; Mediating; Microbe; Modeling; Molecular; Mucosal Immune Responses; Mucous Membrane; Mus; Nature; Pathogenesis; Pattern; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Publishing; Research Personnel; Role; Salmonella; Shigella; Signal Pathway; Signal Transduction; Signal Transduction Pathway; TLR5 gene; Toll-Like Receptor 5; Toll-like receptors; Yersinia; commensal microbes; intestinal epithelium; microbial; microorganism; mouse model; pathogen; prevent; programs; receptor; research study; response

The human gut harbors a large collection of commensal microbes. Several clinical observations and animal experiments suggested that intestinal bacteria play a major role in the pathogenesis of chronic bowel inflammation. Enteroinvasive pathogens such as Salmonella, Shigella, Yersinia, and Listeria can invade the epithelium and provoke inflammatory responses. Flagellin, a major component of bacterial flagellar, is released from various bacteria, including commensal or enteroinvasive microbes, and stimulates Toll-like receptor (TLR) 5 that is highly expressed in intestinal epithelium. Our recent results showed in non- transformed human colonocytes, as well as normal human colon that flagellin stimulation specifically induces proinflammatory gene expression, a prominent characteristic of the pathophysiology of IBD. In spite of these findings, the mechanisms by which bacterial flagellin signals proinflammatory responses in colonocytes and native colonic mucosa remain poorly understood. The central hypothesis of this proposal is that compromised epithelial barrier function, either by injury or by erosive pathogens, enables bacterial flagellin to penetrate the leaky epithelium and activate basolateral TLR5 leading to colonic inflammation. Our goals are to elucidate the signaling pathways by which flagellin exert its proinflammatory action(s) in human colonocytes and examine the participation of bacterial flagellin in the development and progress of colonic inflammation in mouse colitis models. Aim 1 will study the signal transduction pathway(s) leading to IL-8 and MIP-3a gene expression in response to flagellin in non-transformed human colonic NCM460 cells. In this aim we will identify the specific kinase(s) involved in MEK phosphorylation in response to flagellin exposure and examine their involvement in TLR5-dependent IL-8 and MIP-3a gene expression. Experiments to determine the signaling mechanism(s) by which the phosphatase MKP-1 amplifies flagellin-induced proinflammatory responses are also proposed. Aim 2 will examine the role of PI-3K signaling in TLR5-associated IL-8 and MIP-3a gene expression in human colonocytes. Aim 3 will examine the role of flagellin in the progress of colitis using mouse models of colitis and determine whether the basolateral or luminal aspect of the human and mouse colonic mucosa is responsive to flagellin. Our proposed studies will provide significant information relevant to the pathogenesis of colonic inflammation, including IBD.

人类肠道内有大量的肠道微生物。一些临床观察和动物 实验表明，肠道细菌在慢性肠道疾病的发病机制中起主要作用， 炎症肠道侵入性病原体如沙门氏菌、志贺氏菌、耶尔森氏菌和李斯特菌可侵入肠道， 上皮并引起炎症反应。鞭毛蛋白是细菌鞭毛的主要成分， 从各种细菌中释放，包括肠道或肠道侵入性微生物，并刺激Toll样 受体（TLR）5在肠上皮中高度表达。我们最近的结果显示，在非- 转化的人结肠细胞以及鞭毛蛋白刺激特异性诱导的正常人结肠 促炎基因表达，IBD的病理生理学的突出特征。尽管有这些 研究发现，细菌鞭毛蛋白在结肠细胞中发出促炎反应信号的机制， 对天然结肠粘膜仍知之甚少。这一提议的核心假设是， 损伤或侵蚀性病原体导致的上皮屏障功能受损，使细菌鞭毛蛋白能够 穿透渗漏的上皮并激活基底外侧TLR 5，导致结肠炎症。我们的目标是 为了阐明鞭毛蛋白在人类中发挥其促炎作用的信号通路， 探讨鞭毛蛋白在结肠癌发生发展中的作用 小鼠结肠炎模型中的炎症。目的1将研究导致IL-8的信号转导途径， MIP-3a基因在非转化的人结肠NCM 460细胞中响应鞭毛蛋白的表达。在这一目标中， 我们将鉴定参与响应鞭毛蛋白暴露的MEK磷酸化的特异性激酶， 检测它们参与TLR 5依赖性IL-8和MIP-3a基因表达。实验以确定 磷酸酶MKP-1放大鞭毛蛋白诱导的促炎症反应的信号传导机制 并提出了对策。目的2将研究PI-3 K信号在TLR 5相关IL-8和IL-10中的作用。 人结肠细胞MIP-3a基因表达。目的3将研究鞭毛蛋白在细胞凋亡过程中的作用。 使用结肠炎的小鼠模型，并确定人结肠炎的基底外侧或管腔方面是否与结肠炎的基底外侧或管腔方面相关。 并且小鼠结肠粘膜对鞭毛蛋白有反应。我们的研究将提供重要的 与结肠炎症（包括IBD）的发病机制相关的信息。