The molecular mechanism of te pathogenesis induced by Helicbacter phylori (TN2) and the clinical application

幽门螺杆菌（TN2）致病的分子机制及临床应用

• 批准号: 11557040
• 负责人: OMATA Masao
• 金额: $ 8.19万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557040/
• 关键词: Helicobacter pylori; intracellular signaling pathways; cagPAI; Mongolian gerbil infection model; microarray; CagA; cagPAI; CagPAI; マイクロアレイ; 胃炎; リン酸化

(1) NF-kB activation by H. pyloriWe analyzed the molecular mechanism of H. pylori-mediated NF-kB activation in both a gastric epithelial cell line and in a monocytic cell line.In gastric cancer cells, H. pylori possessing intact cag PAI activates NF-kB through a signaling pathway involving IkB kinases (IKK's), NF-kB-inducing kinase (NIK), TRAF2, and TRAF6. In a monocytic cell line, H. pylori-mediated NF-kB activation involves TLR4 but is independent of cag PAI.(2) The activation of ERK/MARK cascade by H. pyloriH. pylori with intact cage PAI activated SRE, c-fos and Cyclin D1 transcription through the activation of ERK/MAPK cascade in human gastric cancer cells.(3) SRE activation by CagA proteinIt has been reported that CagA protein is translocated into epithelial cells and associated with cellular cytoskeletal rearrangements. We identified a new role of CagA protein as an activator of SRE.(4) cDNA microarray analysis of H. pylori-mediated alteration of gene expressionWe compared mRNA profiles in human gastric cancer cells with and without H. pylori cocultured by using an in-house cDNA microarray. Coculture with cag PAI positive strain significantly up-regulated mRNA expression in 8 of 2304 genes fested.(5) Mongolian gerbil infection modelWe examined the role of cag PAI in the gastric pathogenesis induced by H. pylori using a long-term (62 wk) animal model. Mongolian gerbils were challenged with TN2 and its isogenic mutants of cagE or vacA. No ulcer was found in the gerbils infected with the cagE mutant, and cagE mutants induced only mild gastritis cag PAI plays an essential role in the pathogenesis of gastric diseases related H. pylori infection.Furthermore, we validated a 3-week gerbil model using isogenic mutants for screening of proinflammatory virulence determinants of H. pylori in vivo.

(1)H. pylori感染的分子机制。幽门螺杆菌介导的NF-κ B活化在胃上皮细胞系和单核细胞系中的表达。具有完整cag派的幽门螺杆菌通过涉及IkB激酶（IKK）、NF-κ B诱导激酶（NIK）、TRAF 2和TRAF 6的信号传导途径激活NF-κ B。在单核细胞系中，H. pylori介导的NF-kB激活涉及TLR 4，但不依赖于cag派。(2)H. pylori H. pylori通过激活ERK/MAPK级联反应激活人胃癌细胞SRE、c-fos和Cyclin D1的转录。(3)CagA蛋白激活SRE据报道，CagA蛋白移位到上皮细胞中并与细胞骨架重排相关。我们确定了CagA蛋白作为SRE激活剂的新作用。(4)cDNA微阵列分析H. pylori介导的基因表达改变我们比较了有和没有H. pylori共培养，通过使用内部cDNA微阵列。与cag派阳性菌株共培养后，2304个基因中有8个基因的mRNA表达显著上调。(5)本实验研究了cag派在H.幽门螺杆菌使用长期（62周）动物模型。用TN 2及其cagE或vacA等基因突变体攻击长爪沙鼠。cagE突变体感染沙鼠后无溃疡发生，仅引起轻度胃炎，派在H.此外，我们验证了一个3周的沙鼠模型，使用同基因突变体筛选H. pylori的促炎毒力决定因子。pylori in vivo.

项目成果

Maeda S, et al: "H. pylori Activates NF-αB Through a Signaling Pathway Involving IB Kinases, NF-B-Inducing Kinase, TRAF2, and TRAF6 in Gastric Cancer Cells"Gastroenterology. 119. 97-108 (2000)

Maeda S 等人：“幽门螺杆菌通过胃癌细胞中涉及 IB 激酶、NF-B 诱导激酶、TRAF2 和 TRAF6 的信号通路激活 NF-αB”Gastroenterology。

Yoshida H, Hirota K, Ogura K, Maeda S, Shiratori Y, Sasaki Y, Omata M: "Determination of the optimal cut-off value for [13C]urea breath test based on a Helicobacter pylori-specific PCR assay"J. gastroenterol Hepatol. 15. 155-160 (2000)

Yoshida H、Hirota K、Ogura K、Maeda S、Shiratori Y、Sasaki Y、Omata M：“基于幽门螺杆菌特异性 PCR 测定确定 [13C] 尿素呼气试验的最佳截止值”J。

Maeda S, Yoshida H. Ogura K, Yamaji Y, Ikenoue T, Mitsushima T, Tagawa H, Kawaguchi R, Mori K,m Mafune K, Kawabe T, Shiratori Y, Omata M: "Assessment of gastric carcinoma risk associated with helicobactoer pylori may vary depending on the antigen used - C

Maeda S、Yoshida H. Ogura K、Yamaji Y、Ikenoue T、Mitsushima T、Takawa H、Kawaguchi R、Mori K、m Mafune K、Kawabe T、Shiratori Y、Omata M：“与幽门螺杆菌相关的胃癌风险评估

Maeda S, et al.: "H. pylori activates NF-kappa B through a signaling pathway involving I kappa B kinases, NF-kappa B inducing kinase, TRAF2, and TRAF6 in gastric cancer cells"Gastroenterology. 119. 97-108 (2000)

Maeda S 等人：“幽门螺杆菌通过涉及胃癌细胞中 I kappa B 激酶、NF-kappa B 诱导激酶、TRAF2 和 TRAF6 的信号传导途径激活 NF-kappa B”。

Ogura K, Yoshida H, Maeda S, Yamaji Y, Kawabe T, Okamoto M, Shiratori Y, Omata M: "Clarithromycin-based triple therapy for non-resistant helicobacter pylori infection : How long should it be given?"Scand J Gastroenterol.. 36. 584-588 (2001)

Ogura K、Yoshida H、Maeda S、Yamaji Y、Kawabe T、Okamoto M、Shiratori Y、Omata M：“基于克拉霉素的三联疗法治疗非耐药性幽门螺杆菌感染：应该给予多长时间？”Scand J Gastroenterol。