Molecular mechanisms underlying gastrointestinal lesions in transgenic mice expressing Helicobacter pylori cagA gene

• Project/Area Number: 17390211
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: HOKKAIDO UNIVERSITY
• Principal Investigator: HATAKEYAMA Masanori HOKKAIDO Univ., Inst. for Genetic Med., Prof., 遺伝子病制御研究所, 教授 (40189551)
• Co-Investigator(Kenkyū-buntansha): AZUMA Takeshi KOBE Univ., School of Mcd., Prof., 医学部, 教授 (60221040)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥14,600,000 (Direct Cost: ¥14,600,000); Fiscal Year 2006: ¥5,900,000 (Direct Cost: ¥5,900,000); Fiscal Year 2005: ¥8,700,000 (Direct Cost: ¥8,700,000)
• Keywords: Helicobacter pylori / CagA / transgenic mouse / Western CagA / East Asian CagA / gastric mucosal lesion / tyrosine phosphory lation / EPIYA / 胃粘膜 / EPIYAモチーフ / 胃癌

Research Abstract

Infection with Helicobacter pylori is associated with chronic gastritis and peptic ulcers. In particular, H. pylori cagA-positive strains causes severe gastritis and have been suggested to play an important role in the development of gastric carcinoma. To investigate the direct role of H. pylori CagA in carcinogenesis, we generated transgenic mice that express ABDD-type East Asian CagA specifically in the gastric mucosa or throughout the body. Both of the CagA transgenic mice developed thickened gastric mucosa with epithelial cell hyperproliferation by 12 weeks of age. The findings indicate that CagA has a growth-promoting activity in a tissue-specific manner in vivo. To know if the CagA activity is dependent on CagA tyrosine phosphorylation, we generated transgenic mice that express a phosphorylation-resistant CagA, which was made by replacing the EPIYA tyrosine-phosphorylation motifs with the EPIYA sequences in the ABDD-type CagA. To understand the relationship between structural polymorphism and in vivo pathogenicity of CagA proteins, we also generated transgenic mice that express ABCCC-type Western CagA. Development of gastrointestinal lesions in these transgenic mice is currently under investigation.
Sequence analysis of the genes encoding East Asian CagA proteins from various clinical isolates revealed that there is also significant structural diversity among East Asian CagA species due to various genomic duplication and/or deletion, which was not recognized previously. Functional studies of these East Asian CagA proteins showed that the degree of individual CagA to bind SHP-2 depends on the number of EPIYA-D sites whereas that of CagA-Csk interaction is dependent on the number of EPIYA-A and-B sites.

Research Products

• [Journal Article] Helicobacter pylori CagA associates with E-cadherin and deregulates β -catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. (2007)
  • Author(s): Murata-Kamiya, N., Kurashima, Y., Tcishikata, Y., Yamahashi, Y., Saito, Y., Higashi, H., Aburatani, H., Peek, R.M., Jr., Azuma, T., Hatakeyama., M.
  • Journal Title: Oncogene (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. (2006)
  • Author(s): Murata-Kamiya, N.
  • Journal Title: Oncogene (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Structural basis and functional consequence of Helicobacter pylori CagA multimerization in cells. (2006)
  • Author(s): Ren, S.
  • Journal Title: J. Biol. Chem. 281 Pages: 32344-32352
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of Helicobacter pylori CagA in gastric carcinogenesis. (2006)
  • Author(s): Hatakeyama, M.
  • Journal Title: Int. J. Hematol. 84 Pages: 301-308
  • NAID: 10019259495
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Development of a novel method to detect Helicobacter pylori cagA genotype from paraffin-embedded materials : comparison between patients with duodenal ulcer and gastric vancer in young Japanese. (2006)
  • Author(s): Ueda, H.
  • Journal Title: Digestion 732 Pages: 47-53
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pathogenesis of Helicobacter pylori infection. (2006)
  • Author(s): Hatakeyama, M.
  • Journal Title: Helicobacter 11
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. (2006)
  • Author(s): Naito, M.
  • Journal Title: Gastroenterolory 130 Pages: 1181-1190
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori CagA - a bacterial intruder conspiring gastric carcinogenesis. (2006)
  • Author(s): Hatakeyama, M.
  • Journal Title: Int. J. Cancer 119 Pages: 1217-1223
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. (2006)
  • Author(s): Tsutsumi, R.
  • Journal Title: Mol. Cell. Biol. 26 Pages: 261-276
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ピロリ菌の生態と最新研究。 (2006)
  • Author(s): 畠山 昌則
  • Journal Title: 化学 61 Pages: 18-20
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ピロリ菌と胃潰瘍・胃癌-検査とのかかわり。 (2006)
  • Author(s): 湯浅 眸
  • Journal Title: 検査と技術 34 Pages: 802-805
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ヘリコバクター・ピロリ感染と胃癌。 (2006)
  • Author(s): 畠山 昌則
  • Journal Title: Cancer Frontier 8 Pages: 98-106
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ヘリコバクター・ピロリ病原因子CagAと胃癌。 (2006)
  • Author(s): 畠山 昌則
  • Journal Title: 化学と生物 44 Pages: 681-687
  • NAID: 10018252529
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Structural basis and functional consequence of Helicobacter pylori CagA multimerization in Cells. (2006)
  • Author(s): Ren, S., Higashi, H., Lu, H., Azuma, T., Hatakeyama, M.
  • Journal Title: J. Biol. Chem. 281 Pages: 32344-32352
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Development of a novel method to detect Helicobacter pylori cagA genotype from paraffin-embedded materials : comparison between patients with duodenal ulcer and gastric cancer in voune Japanese. (2006)
  • Author(s): Ueda, H., Ito, M, Eguchi, H., Tanaka, S.,.Yoshihara, M., haruma, K., Hatakeyama, M., Chayama, K.
  • Journal Title: Digestion 73 Pages: 47-53
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pathogenesis of Helicobacter pylori infection. (2006)
  • Author(s): Hatakeyama, M., Brzozowski, T.
  • Journal Title: Helicobacter 11, Suppl 1 Pages: 14-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. (2006)
  • Author(s): Naito, M., Yamazaki, T., Tsutsumi, R., Higashi, H., Onoe, K., Yamazaki, S., Azuma, T., Hatakeyama, M.
  • Journal Title: Gas' terolory 130 Pages: 1181-1190
  • NAID: 120000953487
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori CagA・a bacterial intruder conspiring gastric carcinogenesis. (2006)
  • Author(s): Hatakeyama, M.
  • Journal Title: Int..1. Cancer 119 Pages: 1217-1223
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. (2006)
  • Author(s): Tsutsumi, R., Takahashi, A., Azuma, A., Higashi, H., Hatakeyama.M.
  • Journal Title: Mol. Cell. Biol. 26 Pages: 261-276
  • NAID: 120000957433
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori CagA Deregulates the Cell Signaling. (2006)
  • Author(s): Higashi H., Hatakeyama M.
  • Journal Title: Recent Advances in Gastrointestinal Carcinogenesis, (Editors : Hiromi Banba and Shinichi Ota) (TRANSWORLD RESEARCH NETWORK) 13
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori CagA associates with E-cadherin and deregulates β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. (2006)
  • Author(s): Murata-Kamiya, N.
  • Journal Title: Oncogene (in press)
• [Journal Article] Development of a novel method to detect Helicobacter pylori CagA genotype from paraffin-embedded materials : comparison between patients with duodenal ulcer and gastric cancer in young Japanese. (2006)
  • Author(s): Ueda, H.
  • Journal Title: Digestion 732 Pages: 47-53
• [Journal Article] Helicobacter pylori CagA-a bacterial intruder conspiring gastric carcinogenesis. (2006)
  • Author(s): Hatakeyama, M.
  • Journal Title: Int. J. Cancer 119 Pages: 1217-1223
• [Journal Article] Focal adhesion kinase is a substrate and qownstream effector of SHP-2 complexed with Helicobacter pylori CagA. (2006)
  • Author(s): Tsutsumi, R.
  • Journal Title: Mol. Cell. Biol. 26 Pages: 261-276
• [Journal Article] Helicobacter pylori感染と胃癌。 (2006)
  • Author(s): 畠山 昌則
  • Journal Title: Bio Clinica 21 Pages: 1064-1069
• [Journal Article] Influence of EPIYA-repeat Polymorphism on the Phosphorylation-dependent Biological Activity of Helicobacter pylori CagA. (2006)
  • Author(s): Naito, M.
  • Journal Title: Gastroenterolory
• [Journal Article] Helicobacter pylori CagA - a bacterial intruder conspiring gastric carcinogenesis. (2006)
  • Author(s): Hatakeyama, M.
  • Journal Title: Int.J.Cancer
• [Journal Article] Focal Adhesion Kinase Is a Substrate and Downstream Effector of SHP-2 Complexed with Helicobacter pylori CagA. (2006)
  • Author(s): Tsutsumi, R.
  • Journal Title: Mol.Cell.Biol. 26 Pages: 261-276
• [Journal Article] ピロリ菌の生態と最新研究 (2006)
  • Author(s): 畠山 昌則
  • Journal Title: 化学 61 Pages: 18-20
• [Journal Article] Helicobacter pylori CagA - a new paradigm for bacterial carcinogenesis. (2005)
  • Author(s): Hatakeyama, M.
  • Journal Title: Cancer Sci. 96 Pages: 835-843
  • NAID: 10017103932
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Downregulation of cyclin-dependent kinase inhibitor ; p57(kip2), is involved in the cell cycle progression of vascular smooth muscle cells. (2005)
  • Author(s): Nakano, N.
  • Journal Title: Biochem. Biophys. Res. Commun. 338 Pages: 1661-1667
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene. (2005)
  • Author(s): Yanagihara, M.
  • Journal Title: Oncogene 24 Pages: 5878-5887
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. (2005)
  • Author(s): Yokoyama, K.
  • Journal Title: Proc. Natl. Acad. Sci. USA 102 Pages: 9661-9666
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] EPIYA motif is a membrane-targeting singnal of Helicobacter pylori virulence factor CagA in mammalian cells. (2005)
  • Author(s): Higashi, H.
  • Journal Title: J. Biol. Chem. 280 Pages: 23130-23137
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Activation of beta-catenin by carcinogenic Helicobacter pylori. (2005)
  • Author(s): Franco, A. T.
  • Journal Title: Proc. Natl. Acad. Sci. USA 102 Pages: 10646-10651
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Distinct diversity of vacA, cagA, and cagE genes of Helicobacter pylori associated with peptic ulcer in Japan. (2005)
  • Author(s): Yamazaki, S.
  • Journal Title: J. Clin. Microbiol. 43 Pages: 3906-3916
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of Helicobacter pylori and the cagA genotype in gastric biopsies using higly sensitive real-time PCR as a new diagnostic tool. (2005)
  • Author(s): Yamazaki, S.
  • Journal Title: FEMS Immunol. Med. Microbiol. 44 Pages: 261-268
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] H. pylori感染による胃発癌機序。 (2005)
  • Author(s): 畠山 昌則
  • Journal Title: 消化器科 41 Pages: 389-397
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori CagA-SHP-2相互作用と胃癌。 (2005)
  • Author(s): 畠山 昌則
  • Journal Title: 日本臨床 63 Pages: 48-52
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori感染と胃がん。 (2005)
  • Author(s): 畠山 昌則
  • Journal Title: 分子細胞治療 4 Pages: 373-379
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori CagAとSHP-2チロシンホスファターゼ。 (2005)
  • Author(s): 堤 良平
  • Journal Title: 生化学 77 Pages: 1269-1273
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 胃癌発症におけるヘリコバクター・ピロリ菌病原因子CagAの役割。 (2005)
  • Author(s): 内藤 正規
  • Journal Title: Cancer Frontier 7 Pages: 144-149
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori感染による胃発がん機構。 (2005)
  • Author(s): 高橋 昌史
  • Journal Title: がん分子標的治療 3 Pages: 74-79
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ヘリコバクター・ピロリの分子生物学。 (2005)
  • Author(s): 紙谷 尚子
  • Journal Title: 化学療法の領域 21 Pages: 25-31
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori CagA・a new paradigm for bacterial carcinogenesis. (2005)
  • Author(s): Hatakeyama, M., Higashi, H.
  • Journal Title: Cancer Sci. 96 Pages: 835-843
  • NAID: 10017103932
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Downregulation of cyclin-dependent kinase inhibitor ; p57(kip2), is involved in the cell cycle progression of vascular smooth muscle cells. (2005)
  • Author(s): Nakano, N., Urasawa, K., Takagi, Y., Saito, T., Kaneta, S., Ishikaw:4, S, Higashi, H., Tsutsui, H., Hatakeyama.M., Kitabatal:e, A.
  • Journal Title: Biochem. Biophys. Rcs. Commun. 338 Pages: 1661-1667
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene. (2005)
  • Author(s): Yanagihara, M., Ishikawa, S., Naito, M., Nakajima, J., Aburatani, H., Hatakeyama, M.
  • Journal Title: Oncogene 24 Pages: 5878-5887
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. (2005)
  • Author(s): Yokoyama, K., Higashi, H., Ishikawa, S., Fujii, Y., Kondo, S., Kato, 1-1., Azuma, T., Wada, A., Hirayama, T., Aburatani, H., Hatakeyama, M.
  • Journal Title: Proc. Natl. Acad. Sci. USA 102 Pages: 9661-9666
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] EPlYA motif is a membrane-targeting signal of Helicobacter pylori virulence factor CagA in mammalian cells. (2005)
  • Author(s): Higashi, H., Yokoyama, K., Fujii, Y., Ren, S., Yuasa, H., Isaadat, I., Murata-Kamiya, N., Azuma, T., Hatakeyama, M.
  • Journal Title: J. Biol. Chem. 280 Pages: 23130-23137
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Activation of beta-catenin by carcinogenic Helicobacter pylori. (2005)
  • Author(s): Franco, A.T., Israel, D.A., Washington, M.K., Krishna.U..Fox, J.G., Rogers, A.B., Neish, A.S., Collier-Hyams, L., Perez-Perez, G.1., Hatakevama, M..Whitehead, R., gaus, K., O'brien, D.P., Romero-Gallo, J., Peek, R.M.,.Jr.
  • Journal Title: Proc. Natl. Acad. Sci. USA 102 Pages: 10646-10651
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Distinct diversity of vacA, cagA and cagE genes of Helicobacter pylori associated with peptic ulcer in Japan. (2005)
  • Author(s): Yamazaki, S., Yamakawa, A., Okuda, T., Ohtani, M., Suto, H., Ito, Y., Yamazaki, Y., Keida, Y., Higashi, H., Hatakcevama.M., Azuma, T., Distinct diversity of vacA, cagA
  • Journal Title: J. Clin. Microbiol. 43 Pages: 3906-3916
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of Helicobacter pylori and the cagA genotype in gastric biopsies using higly sensitive real-time PCR as a new diagnostic tool. FEMS Immunol. (2005)
  • Author(s): Yamazaki, S., Kato, S., Matsukura, N., Ohtani, M., Ito, Y., Suto, H., Yamazaki, Y., Yamakawa, A., Tokudome, S., Higashi, H., Hatakeyama.M., Azuma, T.
  • Journal Title: FEMS Immunol. Med. Microbiol. 44 Pages: 261-268
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Downregulation of cyclin-dependent kinase inhibitor ; p57(kip2), is involved in the cell cycle progression of vascular smooth muscle cells. (2005)
  • Author(s): Nakano, N.
  • Journal Title: Biochem.Biophys.Res.Commun. 338 Pages: 1661-1667
• [Journal Article] Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NEAT signaling pathway in gastric epithelial cells. (2005)
  • Author(s): Yokoyama, K.
  • Journal Title: Proc.Natl.Acad.Sci.USA 102 Pages: 9661-9666
• [Journal Article] EPIYA motif is a membrane-targeting singnal of Helicobacter pylori virulence factor CagA in mammalian cells. (2005)
  • Author(s): Higashi, H.
  • Journal Title: J.Biol.Chem. 280 Pages: 23130-23137
• [Journal Article] Activation of beta-catenin by carcinogenic Helicobacter pylori. (2005)
  • Author(s): Franco, A.T.
  • Journal Title: Natl.Acad.Sci.USA 102 Pages: 10646-10651
• [Journal Article] Distinct diversity of vacA, cagA, and cagE genes of Helicobacter pylori associated with peptic ulcer in Japan. (2005)
  • Author(s): Yamazaki, S.
  • Journal Title: J.Clin.Microbiol. 43 Pages: 3906-3916
• [Journal Article] Identification of Helicobacter pylori and the cagA genotype in gastric biopsies using higly sensitive real-time PCR as a new diagnostic tool. (2005)
  • Author(s): Yamazaki, S.
  • Journal Title: FEMS Immunol.Med.Microbiol. 44 Pages: 261-268
• [Journal Article] ヘリコバクター・ピロリの分子生物学 (2005)
  • Author(s): 紙谷 尚子
  • Journal Title: 化学療法の領域 21 Pages: 25-31
• [Journal Article] Helicobacter pylori感染による胃発がん機構 (2005)
  • Author(s): 高橋 昌史
  • Journal Title: がん分子標的治療 3 Pages: 74-79
• [Journal Article] 胃癌発症におけるヘリコバクター・ピロリ菌病原因子CagAの役割 (2005)
  • Author(s): 内藤 正規
  • Journal Title: Cancer Frontier 7 Pages: 144-149
• [Journal Article] Helicobacter pylori CagAとSHP-2チロシンポスファターゼ (2005)
  • Author(s): 堤 良平
  • Journal Title: 生化学 77 Pages: 1269-1273
• [Journal Article] Helicobacter pylori感染と胃がん (2005)
  • Author(s): 畠山 昌則
  • Journal Title: 分子細胞治療 4 Pages: 373-379
• [Journal Article] Helicobacter pylori CagA-SHP-2相互作用と胃癌 (2005)
  • Author(s): 畠山 昌則
  • Journal Title: 日本臨床 63 Pages: 48-52
• [Book] バイオとナノの融合II新生命科学の応用 (2007)
  • Author(s): 畠山 昌則
  • Total Pages: 25
  • Publisher: 北海道大学出版会
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Recent Advances in Gastrointestinal Carcinogenesis (2006)
  • Author(s): Higashi, H.
  • Total Pages: 13
  • Publisher: TRANSWORLD RESEARCH NETWORK
  • Description: 「研究成果報告書概要(和文)」より
• [Book] がん研究の今-1. 発がんの分子機構と防御 (笹月健彦、野田哲生編) (2006)
  • Author(s): 畠山 昌則
  • Total Pages: 15
  • Publisher: 東大出版会
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 別冊・医学のあゆみ消化管疾患Ver.3-state of arts.I.消化管(食道・胃・腸) (2006)
  • Author(s): 畠山 昌則
  • Total Pages: 3
  • Publisher: 医歯薬出版(株)
  • Description: 「研究成果報告書概要(和文)」より
• [Book] がん研究の今-1.発がんの分子機構と防御 笹月健彦、野田哲生編 (2006)
  • Author(s): 畠山 昌則
  • Total Pages: 15
  • Publisher: 東大出版会
• [Book] 別冊・医学のあゆみ 消化管疾患 Ver.3-state of arts.I. (2006)
  • Author(s): 畠山 昌則
  • Total Pages: 3
  • Publisher: 医歯薬出版(株)
• [Book] わかる実験医学シリーズ「癌のシグナル伝達」がわかる (2005)
  • Author(s): 大西 なおみ
  • Total Pages: 7
  • Publisher: 羊土社
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 国際特許権 (2005)
  • Inventor(s): 畠山昌則
  • Industrial Property Rights Holder: 北海道大学
  • Filing Date: 2005-07-01
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 国際特許権 (2005)
  • Inventor(s): 畠山昌則
  • Industrial Property Rights Holder: 北海道大学
  • Filing Date: 2005-07-01