Roles of p40phox in Crohn disease and its application for drug development

• Project/Area Number: 23659137
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Kobe University
• Principal Investigator: SAITOU Naoaki 神戸大学, 自然科学系先端融合研究環バイオシグナル研究センター, 教授 (60178499)
• Co-Investigator(Kenkyū-buntansha): UEYAMA Takehiko 神戸大学, 自然科学系先端融合研究環バイオシグナル研究センター, 准教授 (80346254) ; 楠 正人 三重大学, 医学(系)研究科(研究院), 教授 (50192026)
• Co-Investigator(Renkei-kenkyūsha): KUSUNOKI Masato 三重大学, 医学(系)研究科(研究院) (50192026)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: クローン病 / p40phox / 活性酸素 / NADPH / oxidase / 遺伝子異常 / 乳幼児 / オートファジー / モデルマウス / 遺伝子解析

Research Abstract

On the basis of our hypothesis that the etiology of Crohn’s disease is related with that of CGD enteritis due to p40phox gene abnormality, we examined the new cause of Crohn disease and its treatment. We examined the production of reactive oxygen, and p40phox gene mutations in treatment-resistant of the six cases the (refractory) patients with Crohn's disease, but we were not able to discover the CGD enteritis patients due to p40phox gene abnormality.

Research Products

• [Journal Article] Both C1B domain and pseudosubstrate region are necessary for saturated fatty acidmembrane; distinct role of intramolecular domains for different translocation (2013)
  • Author(s): Nishimoto, T., Kashiwagi, K., Saito, N., and Shirai, Y
  • Journal Title: Biochem Biophys Res Commun Volume: 432 Pages: 384-388
• [Journal Article] Both C1B domain and pseudosubstrate region are necessary for saturated fatty acid membrane;distinct role of intramolecular domains for different (2013)
  • Author(s): Takaaki Nishimoto, T., Kashiwagi, K., Saito, N., and Shirai, Y.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 432 Issue: 2 Pages: 384-388
  • DOI: 10.1016/j.bbrc.2013.01.048
  • Peer Reviewed
• [Journal Article] Novel PKCα-mediated phosphorylation site(s) on cofilin and their potential role in terminating histamine release (2012)
  • Author(s): Sakuma, M., Shirai, Y., Yoshino, K-I., Kuramasu, M., Nakamura, T., Yanagita, T., Mizuno, K., Hide, I., Nakata, Y., Saito, N.
  • Journal Title: Mol Biol Cell Volume: 23(18) Pages: 3707-3721
• [Journal Article] MARCKS dephosphorylation is involved in bradykinin-induced neurite outgrowth in neuroblastoma SH-SY5Y cells (2012)
  • Author(s): Tanabe A, Shiraishi M, Negishi M, Saito N, Tanabe M, and Sasaki Y
  • Journal Title: J Cell Physiol Volume: 227(2) Pages: 618-629
• [Journal Article] Establishment of a Novel Fluorescence-Based Method to Evaluate Chaperone-Mediated Autophagy in a Single Neuron. (2012)
  • Author(s): Seki, T., Ken-ich Yoshino, K., Tanaka, S., Dohi, E., Onji, T., Yamamoto, K., Hide, I., Paulson, H.L., Saito, N., Sakai, N
  • Journal Title: PLoS ONE Volume: 7(2)
• [Journal Article] c-Abl tyrosine kinase regulates serum-induced nuclear export of diacylglycerol kinase αby phosphorylation at Tyr218 (2012)
  • Author(s): Matsubara, T., Ikeda, M., Kiso, Y., Sakuma, M., Yoshino, K-I., Sakane, F., Merida, I., Saito, N. and Shirai, Y
  • Journal Title: J. Biol. Chem Volume: 287 Pages: 5507-5517
• [Journal Article] Novel PKCalphamediated phosphorylation site(s) on cofilin and their potential role in (2012)
  • Author(s): Sakuma, M., Shirai, Y., Yoshino, K^I., Kuramasu,M., Nakamura, T., Yanagita, T., Mizuno, K.,Hide, I., Nakata, Y., Saito, N.
  • Journal Title: Mol Biol. Cell Volume: 23 Pages: 3707-3721
  • Peer Reviewed
• [Journal Article] MARCKS dephosphorylation is involved in bradykinin-induced neurite outgrowth in neuroblastoma SH-SY5Y cells. (2012)
  • Author(s): Tanabe A, Shiraishi M, Negishi M, Saito N, Tanabe M, and Sasaki Y.
  • Journal Title: J Cell Physiol. Volume: 227 Issue: 2 Pages: 618-629
  • DOI: 10.1002/jcp.22763
  • Peer Reviewed
• [Journal Article] Establishment of a Novel Fluorescence-Based Method to Evaluate Chaperone-Mediated Autophagy in a Single Neuron. (2012)
  • Author(s): Seki, T., Yoshino, K., Tanaka, S., Dohi, E., Onji, T., Yamamoto, K., Hide, I., Paulson, H.L., Saito, N., Sakai, N
  • Journal Title: PLoS ONE Volume: 7
  • Peer Reviewed
• [Journal Article] Cooperation of p40phox with p47phox for Nox2 activation during FcγR-mediated phagocytosis --Mechanism for acquisition of p40phox PI(3)P binding-- (2011)
  • Author(s): Ueyama, T., Nakakita, J., Kobayashi, T., Kobayashi, T., Son, J-h., Sakaguchi, H., Leto, T., and Saito, N
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 40693-40705
• [Journal Article] Molecular pathophysiology of neurodegenerative disease caused by γPKC mutations (2011)
  • Author(s): Sakai, N., Saito, N. and Seki, T
  • Journal Title: World J. Biological Psychiatry Volume: 12(S1) Pages: 95-98
• [Journal Article] Elucidation of the Molecular Mechanism and Exploration of Novel Therapeutics for Spinocerebellar Ataxia Caused by Mutant Protein Kinase Cγ (2011)
  • Author(s): Seki, T., Adachi, N., Abe-Seki, N., Shimahara, T., Takahashi, H., Yamamoto, K., Saito, N. and Sakai, N
  • Journal Title: J Pharmacol Sci Volume: 116 Pages: 239-247
  • NAID: 10029894921
• [Journal Article] Streptococcus mutans diacylglycerol kinase homologue:a potential target for anti-caries chemotherapy (2011)
  • Author(s): Shibata, Y., Kawada-Matsuo, M., Shirai, Y., Saito, N.,Li. D., and Yamashita, Y
  • Journal Title: J. Med. Microbiol Volume: 60 Pages: 625-630
• [Journal Article] Direct binding of RalA to PKCη and its crucial role in morphological change during keratinocytes differentiation (2011)
  • Author(s): Shirai, Y., Morioka, S., Sakuma, M., Yoshino, K., Otsuji, C., Sakai, N., Kashiwagi, K., Chida, K., Shirakawa, R., Horiuchi, H., Nishigori, C., Ueyama, T., Saito, N
  • Journal Title: Mol. Biol. Cell Volume: 22 Pages: 1340-1352
• [Journal Article] Nuclear Choline Acetyltransferase Activates Transcription of a High-affinity Choline Transporter (2011)
  • Author(s): Matsuo, A., Bellier, J-P, Nishimura, M., Yasuhara, O., Saito, N. and Kimura, H
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 5836-5845
• [Journal Article] Establishment of a novel fluorescence-based method to evaluate chaperone-mediate autophagy in a singlz neuron (2011)
  • Author(s): Seki, T., Ki Y., Tanaka, S., Dohi, E., Onji, T., Yamamoto, K., Seki T, Yoshino KI, Tanaka S, Dohi E, Onji T, Yamamoto K, Hide, I., Sakai, N. et al.
  • Journal Title: PLoS ONE Volume: 7 Issue: 2 Pages: e31232-e31232
  • DOI: 10.1371/journal.pone.0031232
  • Peer Reviewed
• [Journal Article] c-Abl tyrosine kinase regulates serum-induced nuclear export of diacylglycerol kinase α by phosphorylation at Tyr218 (2011)
  • Author(s): Matsubara, M., Ikeda, M., Kiso, Y., Sakuma, M., Sakane, F., Merida, I, Saito, N., Shirai, Y.
  • Journal Title: J.Biol.Chem Volume: 287 Issue: 8 Pages: 5507-5517
  • DOI: 10.1074/jbc.m111.296897
  • Peer Reviewed
• [Journal Article] Cooperation of p40phox with p47phox for Nox2 activation during Fc{lower case gamma}R-mediated phagocytosis --Mechanism for acquisition of p40phox PI(3)P binding--" (2011)
  • Author(s): Ueyama, T., Nakakita, J., Kobayashi, T., Kobayashi, T., -hyun Son, J-h., Sakaguchi, H., Leto, T., and Saito, N
  • Journal Title: J. Biol. Chem. Volume: 286 Pages: 40693-40705
  • Peer Reviewed
• [Journal Article] Molecular pathophysiology of neurodegenerative disease caused by PKC mutations. (2011)
  • Author(s): Sakai, N., Saito, N. and Seki, T.
  • Journal Title: World J. Biological Psychiatry Volume: 12 Pages: 95-98
  • Peer Reviewed
• [Journal Article] Elucidation of the Molecular Mechanism and Exploration of Novel Therapeutics for Spinocerebellar Ataxia Caused by Mutant Protein Kinase Cγ. (2011)
  • Author(s): Seki, T., Adachi, N., Abe-Seki, N., Shimahara, T., Takahashi, H., Yamamoto, K., Saito, N. and Sakai, N．
  • Journal Title: J Pharmacol Sci Volume: 116 Pages: 239-247
  • NAID: 10029894921
  • Peer Reviewed
• [Journal Article] Streptococcus mutans diacylglycerol kinase homologue:a potential target for anti-caries chemotherapy. (2011)
  • Author(s): Shibata, Y., Kawada-Matsuo, M., Shirai, Y., Saito, N., Li. D., and Yamashita, Y.
  • Journal Title: J. Med. Microbiol. Volume: 60 Pages: 625-630
  • Peer Reviewed
• [Journal Article] Direct binding of RalA to PKC and its crucial role in morphological change during keratinocytes differentiation. (2011)
  • Author(s): Shirai, Y., Morioka, S., Sakuma, M., Yoshino, K., Otsuji, C., Sakai, N., Kashiwagi, K., Chida, K., Shirakawa, R., Horiuchi, H., Nishigori, C., Ueyama, T., Saito, N.
  • Journal Title: Mol. Biol. Cell Volume: 22 Pages: 1340-1352
  • Peer Reviewed
• [Journal Article] Nuclear Choline Acetyltransferase Activates Transcription of a High-affinity Choline Transporter. (2011)
  • Author(s): Matsuo, A., Bellier, J-P, Nishimura, M., Yasuhara, O., Saito, N. and Kimura, H.
  • Journal Title: J. Biol. Chem. Volume: 286 Pages: 5836-5845
  • Peer Reviewed
• [Journal Article] Increased seizure susceptibility in a mouse with diacylglycerol kinase β2 deficiency
  • Author(s): Ishisaka, M., Tsuruma, K., Shimazawa, M., Shirai, Y.,Saito, N., and Hara, H
  • Journal Title: Neuroscience & Medicine
• [Presentation] 黒質線条体系における PKCγの基質の解析:ドパミン遊離におけるβPIX リン酸化の 役割 (2013)
  • Author(s): 白藤 俊彦、上山健彦、吉野健一、足立直子、高橋英之、吾郷由希夫、松田敏夫、齋藤 尚亮
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡(口頭発表・日本語)
• [Presentation] Duox の活性酸素産生機構 (2013)
  • Author(s): 佐久間 恵、上山健彦、ヒン田 猛、齋藤尚亮
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡(口頭発表・日本語)
• [Presentation] Duoxの活性酸素産生機構 (2013)
  • Author(s): 佐久間 恵、上山 健彦、濵田 猛、齋藤 尚亮
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡
• [Presentation] 黒質線条体系における PKCγの基質の解析 (2012)
  • Author(s): 白藤 俊彦、吉野 健一、足立 直子、高橋 英之、香田 健、梨子田 哲明、吾郷 由希夫、松田 敏夫、齋藤 尚亮
  • Organizer: 第121回日本薬理学会近畿部会
  • Place of Presentation: 徳島(口頭発表・日本語)
  • Year and Date: 2012-06-29
• [Presentation] Glial functions of Rho-family small GTPases during cerebellar development and after CNS injury (2012)
  • Author(s): Ueyama,T., Kondoh T., Kohta M., Kohmura,E., Hayashibe,M., Nakamura,T., Sakahara,M., Kassai,H., Nakao,K., Aiba,A. and Saito,N.
  • Organizer: 14th International congress of histochemistry and cytochemistry
  • Place of Presentation: 京都(ポスター・英語)
• [Presentation] Involvment of PKCgamma in neurodegenerative disease (2012)
  • Author(s): Saito, N., Takahashi, H., Shirafuji, T., Adachi, N., Danno, S., Ueyama, T., Seki, T. and Sakai,N
  • Organizer: 14th International congress of histochemistry and cytochemistry
  • Place of Presentation: 京都(ポスター・英語)
• [Presentation] Role of PKCα-mediated cofilin phosphorylation in the degranulation from RBL-2H3 mast cells (2012)
  • Author(s): Sakuma, M., Shirai, Y., Yoshino, K., Kuramasu, M., Nakamura, T., Mizuno, K., Hide,I., Nakata,Y.and Saito,N
  • Organizer: 22th IUBMB & 37th FEBS
  • Place of Presentation: スペイン(ポスター発表・英語)
• [Presentation] DGKbeta による神経突起伸張機構の解析 (2012)
  • Author(s): 加野 拓也、上田 修司、山之上 稔、齋藤尚亮、白井 康仁
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡(ポスター発表・日本語)
• [Presentation] 中枢神経損傷とRho family GTPases (CNS injury and Rho family GTPases) (2012)
  • Author(s): 上山健彦、齋藤尚亮
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都(口頭発表、英語)
• [Presentation] 創薬ターゲットとしてのジアシルグリセロールキナーゼ (2012)
  • Author(s): 白井康仁、齋藤尚亮
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都(口頭発表、英語)
• [Presentation] ジアシルグリセロールキナーゼのヒスタミン分泌制御における役割 (2012)
  • Author(s): 佐久間 恵、白井康仁、上山健彦、齋藤尚亮
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都(ポスター発表、日本語)
• [Presentation] 無血清時における核内 DGKalpha の生理機能 (2012)
  • Author(s): 木曽裕子、白井康仁、佐久間 恵、池田もも、齋藤尚亮
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都(ポスター発表、日本語)
• [Presentation] 細胞内シグナル分子の可視化と細胞機能 (2012)
  • Author(s): 齋藤尚亮
  • Organizer: 第89回日本生理学大会
  • Place of Presentation: 松本(招待講演・日本語)
• [Presentation] Glial functions of Rho-family small GTPases during cerebellar development and after CNS injury (2012)
  • Author(s): Ueyama,T., Kondoh T., Kohta M., Kohmura,E., Hayashibe,M., Nakamura,T.,
  • Organizer: 14th International congress of histochemistry and cytochemistry
  • Place of Presentation: 京都
• [Presentation] Involvment of PKCgamma in neurodegenerative disease (2012)
  • Author(s): Saito, N., Takahashi, H., Shirafuji, T., Adachi, N., Danno, S., Ueyama, T.,
  • Organizer: 14th International congress of histochemistry and cytochemistry
  • Place of Presentation: 京都
• [Presentation] le of PKCalpha-mediated cofilin phosphorylation in the degranulation from RBL-2H3 mast cells. (2012)
  • Author(s): Sakuma, M., Shirai, Y., Yoshino, K., Kuramasu, M., Nakamura, T., Mizuno, K.,
  • Organizer: 22th IUBMB & 37th FEBS
  • Place of Presentation: スペイン
• [Presentation] プロテインキナーゼCのトランスロケーションと酵素活性に対するプロポフェノールの効果 (2011)
  • Author(s): 宮原岳史、関 貴弘、秀 和泉、田中 茂、齋藤尚亮、入船正浩、酒井規雄
  • Organizer: 第120回日本薬理学会近畿部会
  • Place of Presentation: 京都(ポスター発表・日本語)
  • Year and Date: 2011-11-11
• [Presentation] 異なるチロシンリン酸化によるジアシルグリセロールキナーゼ alpha の局在 調節機構 (2011)
  • Author(s): 白井康仁、池田もも、佐久間 恵、木曽裕子、齋藤尚亮
  • Organizer: 第119回日本薬理学会近畿部会
  • Place of Presentation: 名古屋(口頭発表・日本語)
  • Year and Date: 2011-07-08
• [Presentation] Nuclear choline acetyltransferase activates transcription of a high-affinity choline transporter (2011)
  • Author(s): Matsuo,A., J.P.Bellier., Nishimura,M., Yasuhara,O., Saito,N. and Kimura,H
  • Organizer: 8th IBRO worrd congress of neuroscience
  • Place of Presentation: Italy(ポスター発表・英語)
• [Presentation] Novel phosphorylation site(s) of cofilin by PKCalpha contributes to proper termination of histamine release (2011)
  • Author(s): 佐久間 恵、白井康仁、吉野健一、倉増真帆、中村朋文、水野健作、秀 和泉、仲田義啓、齋藤尚亮
  • Organizer: 第84回日本生化学会
  • Place of Presentation: 京都(口頭発表、日本語)
• [Presentation] 部位特異的KOマウスを用いた低分子量Gタンパク質の組織学的機能解析 (2011)
  • Author(s): 上山健彦、齋藤尚亮
  • Organizer: 日本組織細胞化学会年会
  • Place of Presentation: 金沢(招待講演、日本語)
• [Presentation] Novel phosphorylation site(s) of cofilin by PKCα and its negative role in the degranulation from RBL-2H3 mast cells (2011)
  • Author(s): Sakuma,M., Shirai,Y., Yoshino K., Kuramasu,M., Nakamura,T., Mizuno,K., Hide,I., Nakata,Y. and Saito,N
  • Organizer: he American society for cell biology
  • Place of Presentation: デンバー(ポスター発表・英語)
• [Presentation] Novel phosphorylation site(s) of cofilin by PKCalpha and its negative role in the degranulation from RBL-2H3 mast cells. (2011)
  • Author(s): Sakuma,M., Shirai,Y., Yoshino K., Kuramasu, M., Nakamura,T., Mizuno,K., Hide,I., Nakata,Y. and Saito,N.
  • Organizer: The American society for cell biology.
  • Place of Presentation: Denver, USA
• [Presentation] 中枢神経損傷とRho family GTPases
  • Author(s): 上山健彦、齋藤尚亮
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都
• [Presentation] 創薬ターゲットとしてのジアシルグリセロールキナーゼ
  • Author(s): 白井康仁、齋藤尚亮
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都
• [Presentation] 細胞内シグナルの可視化と細胞機能
  • Author(s): 齋藤尚亮
  • Organizer: 第８９日本生理学会大会
  • Place of Presentation: 松本