Toll-like receptors and intestinal inflammation

Toll 样受体与肠道炎症

• 批准号: 7247881
• 负责人: CHARALABOS POTHOULAKIS
• 金额: $ 11.23万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7247881
• 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; Knock-out; 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：人体肠道内含有大量肠道微生物。多项临床观察和动物实验表明，肠道细菌在慢性肠道炎症的发病机制中发挥着重要作用。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上皮并引起炎症反应。鞭毛蛋白（Flagellin）是细菌鞭毛的主要成分，从各种细菌（包括肠道或肠侵袭性微生物）释放，并刺激在肠上皮中高度表达的Toll样受体（TLR）5。我们最近的结果表明，在非转化的人结肠细胞以及正常人结肠中，鞭毛蛋白刺激特异性诱导促炎基因表达，这是IBD病理生理学的一个突出特征。尽管有这些发现，细菌鞭毛蛋白在结肠细胞和天然结肠粘膜中的促炎反应信号的机制仍然知之甚少。该提议的中心假设是，损伤或侵蚀性病原体导致的上皮屏障功能受损，使得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。我们的目标是阐明鞭毛蛋白在人类结肠细胞中发挥其促炎作用的信号通路，并在小鼠结肠炎模型中检查细菌鞭毛蛋白在结肠炎症的发展和进展中的参与。目的1研究鞭毛蛋白诱导人结肠癌NCM 460细胞IL-8和MIP-3a基因表达的信号转导途径。在这个目标中，我们将确定特定的激酶（S）参与MEK磷酸化反应鞭毛蛋白暴露，并检查其参与TLR 5依赖性IL-8和MIP-3a基因表达。还提出了确定磷酸酶MKP-1放大鞭毛蛋白诱导的促炎反应的信号传导机制的实验。目的2研究PI-3 K信号通路在人结肠细胞TLR 5相关IL-8和MIP-3a基因表达中的作用。目的3将使用结肠炎小鼠模型检查鞭毛蛋白在结肠炎进展中的作用，并确定人和小鼠结肠粘膜的基底外侧或管腔方面是否对鞭毛蛋白有反应。我们提出的研究将提供重要的信息相关的结肠炎症的发病机制，包括IBD。