2001 年度実績報告書

Helicobacter pylori菌(TN2)病原性の分子機構解明と臨床応用

研究課題

研究課題/領域番号	11557040
研究機関	東京大学
研究代表者	小俣政男東京大学, 医学部・附属病院, 教授 (90125914)
研究分担者	吉田晴彦東京大学, 医学部・附属病院, 助手 (60240305) 中尾雅文武田薬品工業株式会社, 首席研究員
キーワード	Helicobacter pylori / 細胞内情報伝達 / cagPAI / スナネズミモデル / マクロアレイ / cagA
研究概要	(1)NF-κB活性化の検討炎症や癌化に関与するNF-κBのH. pyloriの共培養によるヒト胃癌細胞での活性化機序の解析を行うと共に、単球系細胞におけるH. pyloriの直接接触を介さない上皮細胞と異なる経路で生じる活性化機序を明らかにした。胃癌細胞においてはcag PAIを有するH. pyloriのみが活性化し、単球系細胞ではcag PAIの有無に関わらず活性化した。 (2)H. pylori感染による細胞増殖シグナルの活性化胃癌細胞でのH. pyloriの共培養による細胞増殖に関わるMAPK、JNK、c-fos、サイクリンD1などの分子のcag PAI依存性の活性化機構を明らかにした。 (3)CagA蛋白による細胞増殖シグナルの活性化 cagPAIが形成するIV型分泌機構をもちいて宿主上皮細胞内に注入され、更にリン酸化されるCagA蛋白が、CagAのC端側(872-950aa)を介しチロシンリン酸化とは独立してElk1をリン酸化しSREの活性化する事が判明した。 (4)H. pylori感染により発現増強する遺伝子のアレイを用いた網羅的解析ヒト胃癌細胞株にH. pyloriを感染させることによって惹起される宿主細胞のmRNAの変化を網羅的に検討するため、2304の遺伝子をスポットしたマイクロアレイをin-houseで作成し、TN2株による8/2304の遺伝子の活性化を検出した。 (5)スナネズミ感染モデル長期感染ではcag PAI陽性の株では慢性活動性胃炎、潰瘍、胃癌を認めたが、cag PAI陰性の株では病理学的変化が乏しく、cag PAIのin vivoにおける病原性が明らかとなった。短期感染でもcag PAIに依存した胃炎を認め、in vivoにおけるH. pyloriの病原因子のスクリーニングに短期感染が有用であることを示した。

研究成果
(17件)

すべてその他

すべて文献書誌 (17件)

[文献書誌] Maeda S, et al.: "Detection of clarithromycin-resistant Helicobacter pylori strains with a preferential homo-duplex formation assay"J Clin Microbiol. 38. 210-214 (2000)
[文献書誌] Asahi M, et al.: "Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells"J Exp Med. 191. 593-602 (2000)
[文献書誌] Yoshida H, et al.: "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)
[文献書誌] Maeda S, et al.: "Assessment of gastric carcinoma risk associated with Helicobacter pylori may vary depending on the antigen used - CagA specific enzyme-linked immunoadsorbent assay (ELISA) versus commercially available H. pylori ELISAs"Cancer. 88. 1530-1535 (2000)
[文献書誌] 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)
[文献書誌] Ogura K, et al.: "Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil"J Exp Med. 192. 1601-1610 (2000)
[文献書誌] Ikenoue T, et al.: "Determination of Helicobacter pylori virulence by simple gene analysis of the cag pathogenicity island"Clin Diagn Lab Immunol. 8. 181-186 (2001)
[文献書誌] Matsumura M, et al.: "Rapid detection of mutations in the 23S rRNA gene of Helicobacter pylori that confers resistance to clarithromycin treatment to the bacterium"J Clin Microbiol. 39. 691-695 (2001)
[文献書誌] Hirata Y, et al.: "Helicobacter pylori activates the cyclin D1 gene through mitogen-activated protein kinase pathway in gastric cancer cells"Infect Immun. 69. 3965-3971 (2001)
[文献書誌] Maeda S, et al.: "cDNA microarray analysis of Helicobacter pylori-mediated alteration of gene expression in gastric cancer cells"Biochem Biophys Res Commun. 284. 443-449 (2001)
[文献書誌] Mitsuno Y, et al.: "Helicobacter pylori induced transactivation of SRE and AP-1 through the ERK signalling pathway in gastric cancer cells"Gut. 49. 18-22 (2001)
[文献書誌] Ogura K, et al.: "Clarithromycin-based triple therapy for non-resistant Helicobacter pylori infection : How long should it be given ?"Scand J Gastroenterol. 36. 584-588 (2001)
[文献書誌] Yamaji Y, et al.: "Inverse background of Helicobacter pylori antibody and pepsinogen in reflux oesophagitis compared with gastric cancer : analysis of 5732 Japanese subjects"Gut. 49. 335-340 (2001)
[文献書誌] Maeda S, et al.: "Distinct mechanism of Helicobacter pylori-mediated NF-kappa B activation between gastric cancer cells and monocytic cells"J Biol Chem. 276. 44856-44864 (2001)
[文献書誌] Akanuma M, et al.: "The evaluation of putative virulence factors of Helicobacter pylori for gastroduodenal disease using short-term Mongolian gerbil infection model"J Infect Dis. 185. 341-347 (2002)
[文献書誌] Yamaji Y, et al.: "Weak response of Helicobacter pylori antibody is high risk for gastric cancer : a cross-sectional study of 10,234 endoscoped Japanese"Scand J Gastroenterol. 37. 148-153 (2002)
[文献書誌] Mitsuno Y, et al.: "Helicobacter pylori activates the proto-oncogene c-fos through SRE transactivation"Biochem Biophys Res Commun. 291(in press). 868-874 (2002)

2001 年度 実績報告書

Helicobacter pylori菌(TN2)病原性の分子機構解明と臨床応用

研究代表者

小俣 政男 東京大学, 医学部・附属病院, 教授 (90125914)

研究成果

[文献書誌] Maeda S, et al.: "Detection of clarithromycin-resistant Helicobacter pylori strains with a preferential homo-duplex formation assay"J Clin Microbiol. 38. 210-214 (2000)

[文献書誌] Asahi M, et al.: "Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells"J Exp Med. 191. 593-602 (2000)

[文献書誌] Yoshida H, et al.: "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)

[文献書誌] Maeda S, et al.: "Assessment of gastric carcinoma risk associated with Helicobacter pylori may vary depending on the antigen used - CagA specific enzyme-linked immunoadsorbent assay (ELISA) versus commercially available H. pylori ELISAs"Cancer. 88. 1530-1535 (2000)

[文献書誌] 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)

[文献書誌] Ogura K, et al.: "Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil"J Exp Med. 192. 1601-1610 (2000)

[文献書誌] Ikenoue T, et al.: "Determination of Helicobacter pylori virulence by simple gene analysis of the cag pathogenicity island"Clin Diagn Lab Immunol. 8. 181-186 (2001)

[文献書誌] Matsumura M, et al.: "Rapid detection of mutations in the 23S rRNA gene of Helicobacter pylori that confers resistance to clarithromycin treatment to the bacterium"J Clin Microbiol. 39. 691-695 (2001)

[文献書誌] Hirata Y, et al.: "Helicobacter pylori activates the cyclin D1 gene through mitogen-activated protein kinase pathway in gastric cancer cells"Infect Immun. 69. 3965-3971 (2001)

[文献書誌] Maeda S, et al.: "cDNA microarray analysis of Helicobacter pylori-mediated alteration of gene expression in gastric cancer cells"Biochem Biophys Res Commun. 284. 443-449 (2001)

[文献書誌] Mitsuno Y, et al.: "Helicobacter pylori induced transactivation of SRE and AP-1 through the ERK signalling pathway in gastric cancer cells"Gut. 49. 18-22 (2001)

[文献書誌] Ogura K, et al.: "Clarithromycin-based triple therapy for non-resistant Helicobacter pylori infection : How long should it be given ?"Scand J Gastroenterol. 36. 584-588 (2001)

[文献書誌] Yamaji Y, et al.: "Inverse background of Helicobacter pylori antibody and pepsinogen in reflux oesophagitis compared with gastric cancer : analysis of 5732 Japanese subjects"Gut. 49. 335-340 (2001)

[文献書誌] Maeda S, et al.: "Distinct mechanism of Helicobacter pylori-mediated NF-kappa B activation between gastric cancer cells and monocytic cells"J Biol Chem. 276. 44856-44864 (2001)

[文献書誌] Akanuma M, et al.: "The evaluation of putative virulence factors of Helicobacter pylori for gastroduodenal disease using short-term Mongolian gerbil infection model"J Infect Dis. 185. 341-347 (2002)

[文献書誌] Yamaji Y, et al.: "Weak response of Helicobacter pylori antibody is high risk for gastric cancer : a cross-sectional study of 10,234 endoscoped Japanese"Scand J Gastroenterol. 37. 148-153 (2002)

[文献書誌] Mitsuno Y, et al.: "Helicobacter pylori activates the proto-oncogene c-fos through SRE transactivation"Biochem Biophys Res Commun. 291(in press). 868-874 (2002)

2001 年度実績報告書

小俣政男東京大学, 医学部・附属病院, 教授 (90125914)