Maintenance of intestinal homeostasis by enteric neuron and mucosal immune system

• Project/Area Number: 25460380
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Chiba University
• Principal Investigator: Hatano Masahiko 千葉大学, 医学(系)研究科(研究院), 教授 (20208523)
• Co-Investigator(Kenkyū-buntansha): FUJUMURA Lisa 千葉大学, バイオメディカル研究センター, 助教 (30376363)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 腸管神経系 / 腸管免疫系 / 腸管上皮バリア / 腸内フローラ / 腸内細菌叢 / 上皮バリア / 一酸化窒素 / 腸管神経 / 炎症性腸疾患 / 腸内細菌 / 腸管免疫 / 腸管上皮細胞 / 遺伝子組換えマウス / nNOS

Outline of Final Research Achievements

Ncx-deficient (KO) mice exhibited increased number of NO producing enteric neurons. We characterized the fecal microbiota to examine whether increased number of enteric neurons affects enteric flora. CFUs of aerobic bacteria increased 10 to 100-folds in the KO mice compared to those of wild type mice.Since bacterial NO reductase gene V (NorV) which detoxificate NO, determine a virulence of bacteria, we further examined frequency of NorV+ bacteria in feces. More NorV+ bacteria were detected from the feces of the KO mice compared to that of wild type mice.To elucidate whether the dysbiosis affect the severity of the DSS-induced colitis, fecal transfer experiments were carried out. C57BL/6 mice were given either wild type or the KO mice derived feces and challenged with DSS. Mice transferred with feces of the KO mice developed more severe colitis than wild type transferred one. Our study implies that NO derived from EN participates in regulation of intestinalhomeostasis.

Research Products

• [Journal Article] DA-Raf-Mediated Suppression of the Ras--ERK Pathway Is Essential for TGF-β1-Induced Epithelial-Mesenchymal Transition in Alveolar Epithelial Type 2 Cells. (2015)
  • Author(s): Watanabe-Takano, H., Takano, K., Hatano, M., Tokuhisa, T. and Endo T.
  • Journal Title: ProS One Volume: 10 Issue: 5 Pages: e0127888-e0127888
  • DOI: 10.1371/journal.pone.0127888
  • Peer Reviewed / Open Access
• [Journal Article] Nepro is localized in the nucleolus and essential for preimplantation development in mice. (2015)
  • Author(s): Masakazu Hashimoto, Tatsuya Sato, Yuko Muroyama, Lisa Fujimura, Masahiko Hatano, Tetsuichiro Saito
  • Journal Title: Development, Growth & Differentiation Volume: 57 Issue: 7 Pages: 529-538
  • DOI: 10.1111/dgd.12232
  • Peer Reviewed
• [Journal Article] Haplpinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1. (2015)
  • Author(s): Matsushita K, Kitamura K, Rahmutulla B, Tanaka N, Ishige T, Satoh M, Hoshino T, Miyagi S, Mori T, Itoga S, SHimada H, Tomonag T, Kito M, Nakajima-Takagi Y, Kubo S, Nakaseko C, Hatano M, Miki T, Matsuo M, Fukuyo M, Kaneda A, Iwama A, Nomura F.
  • Journal Title: Oncotarget Volume: 6 Pages: 5102-5117
  • Peer Reviewed / Open Access
• [Journal Article] Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1. (2015)
  • Author(s): Matsushita, K., Kitamura, K., Rahmutulla, B., Tanaka, N., Ishige, T., Satoh, M., Hoshino, T., Miyagi, S., Mori, T., Itoga, S., Shimada, H., Tomonaga, T., Kito, M., Nakajima-Takagi, Y., Kubo, S., Nakaseko, C., Hatano, M., Miki, T., Matsuo, M., Fukuyo, M., Kaneda, A., Iwama, A., Nomura, F.
  • Journal Title: Oncotarget Volume: 6 Pages: 5102-5117
  • Peer Reviewed / Open Access
• [Journal Article] Plant homeodomain finger protein 11 promotes class switch recombination to IgE in murine activated B cells. (2014)
  • Author(s): Ikari J, Inamine A, Yamamoto T, Watanabe-Takano H, Yoshid a N, Fujimura L, Taniguchi T, Sakamoto A, Hatano M, Tatsumi K, Tokuhisa T, Arima M.
  • Journal Title: Allergy. Volume: 69 Issue: 2 Pages: 223-230
  • DOI: 10.1111/all.12328
  • Peer Reviewed / Open Access
• [Journal Article] DA-Raf-dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation. (2014)
  • Author(s): Watanabe-Takano H, Takano K, Sakamoto A, Matsumoto K, Tokuhisa T, Endo T, Hatano M.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 111 Issue: 22
  • DOI: 10.1073/pnas.1321574111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Generation of tissue-specific H-2K(d) transgenic mice for the study of K(d)-restricted malaria epitope-specific CD8(+) T-cell responses in vivo (2013)
  • Author(s): Huang J, Li X, Kohno K, Hatano M, Tokuhisa T, Murray PJ, Brocker T, and Tsuji M
  • Journal Title: J. Immunol. Methods Volume: 387 Issue: 1-2 Pages: 254-261
  • DOI: 10.1016/j.jim.2012.10.019
  • Peer Reviewed
• [Journal Article] ADAR1 induces adenosine-targeted DNA mutations in senescent Bcl6-deficient cells (2013)
  • Author(s): Tsuruoka, N., Arima, M., Yoshida, N., Okada, S., Sakamoto, A., Hatano, M., Satake, H., Arguni, E., Wang, J.-Y., Yang, J.-H., Nishikura, K., Sekiya, S., Shozu, M. and Tokuhisa, T.
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 2 Pages: 826-836
  • DOI: 10.1074/jbc.m112.365718
  • Peer Reviewed
• [Journal Article] Integration of the mouse sperm fertilization-related protein equatorin into the acrosome during spermatogenesis as revealed by super-resolution and immunoelectron microscopy. (2013)
  • Author(s): Ito, C., Yamatoya, K., Yoshida, K., Fujimura, L., Hatano, M., Miyado, K. and Toshimori, K.
  • Journal Title: Cell Tissue Res. Volume: 352 Pages: 739-750
  • Peer Reviewed
• [Journal Article] Lack of both α2-antiplasmin and plasminogen activator inhibitor type-1 induces high IgE production (2013)
  • Author(s): Okada K, Ueshima S, Kawao N, Yano M, Tamura Y, Tanaka M, Sakamoto A, Hatano M, Arima M, Miyata S, Nagai N, Tokuhisa T, and Matsuo O
  • Journal Title: Life Sci Volume: 93 Issue: 2-3 Pages: 89-95
  • DOI: 10.1016/j.lfs.2013.05.023
  • Peer Reviewed
• [Journal Article] The effect of platelet-rich plasma on posterolateral lumbar fusion in a rat model. (2013)
  • Author(s): Kamoda, H., Ohtori, S., Ishikawa, T., Miyagi, M., Arai, G., Suzuki, M., Sakuma, Y., Oikawa, Y., Kubota, G., Orita, S., Eguchi, Y., Yamashita, M., Yamauchi, K., Inoue, G., Hatano, M. and Takahashi, K.
  • Journal Title: J.Bone Joint Surg.Am. Volume: 95 Issue: 12 Pages: 1109-1116
  • DOI: 10.2106/jbjs.l.00320
  • Peer Reviewed
• [Journal Article] Kinetics and protective role of autophagy in a mouse cecal ligation and puncture-induced sepsis. (2013)
  • Author(s): Takahashi, W., Watanabe, E., Fujimura, L., Watanabe-Takano, H., Yoshidome, H., Swanson, P.E., Tokuhisa, T., Oda, S. and Hatano, M.
  • Journal Title: Crit. Care Volume: 17
  • Peer Reviewed
• [Presentation] Role of enteric neurons in regulation of intestinal homeostasis (2015)
  • Author(s): Lisa Fujimura, Akemi Sakamoto, Masafumi Arima, Takeshi Tokuhisa, Masahiko Hatano
  • Organizer: 第４４回日本免疫学会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2015-11-18
• [Presentation] 腸管恒常性維持における腸管神経の役割について (2015)
  • Author(s): 藤村理紗, 小原由紀子, 大崎敬子, 神谷茂, 幡野雅彦
  • Organizer: 第１９回腸内細菌学会
  • Place of Presentation: 北里大学コンベンションホール（東京都・港区）
  • Year and Date: 2015-06-18
• [Presentation] Role of enteric neurons in regulation of intestinal epithelial homeostasis (2014)
  • Author(s): Fujimura L., Ohara Y., Arima M., Sakamoto A., Tokuhisa T., Hatano M.
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都国際会議場（京都府京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Bcl6 regulates production of SLAM-Associated protein in follicular helper T cells (2013)
  • Author(s): Toshibumi Taniguchi, Akemi Sakamoto, Masahiko Hatano, Kenji Matsumoto, Hirohisa Saito, Takeshi Tokuhisa and Masafumi Arima
  • Organizer: 第42回日本免疫学会
  • Place of Presentation: 千葉・幕張メッセ
• [Presentation] Possible role of enteric neurons in regulation of intestinal microbiota. (2013)
  • Author(s): Lisa Fujimura, Yukiko Ohara, Masafumi Arima, Akemi Sakamoto, Takeshi Tokuhisa and Masahiko Hatano
  • Organizer: 第42回日本免疫学会
  • Place of Presentation: 千葉・幕張メッセ
• [Presentation] 高解像顕微鏡およびSTEDを用いた受精関連タンパク質Equatorinの解析 (2013)
  • Author(s): 伊藤千鶴、大和屋健二、吉田恵一、藤村理紗、幡野雅彦、宮戸健二、年森清隆
  • Organizer: 日本顕微鏡学会第69回学術講演会
  • Place of Presentation: 大阪・ホテル阪急エキスポパーク
• [Presentation] 精子先体赤道部糖タンパク質equqtorinの分子量低下に関わる酵素の探索
  • Author(s): 大和屋健二、伊藤千鶴、陳城、前川眞見子，幡野雅彦、年森清隆
  • Organizer: 第119回日本解剖学会総会・全国学術集会
  • Place of Presentation: 栃木・自治医科大学キャンパス
• [Remarks] 千葉大学バイオメディカル研究センター
  • URL: http://www.m.chiba-u.ac.jp/class/biomedical/
• [Remarks] 千葉大学バイオメディカル研究センター 研究概要
  • URL: http://www.m.chiba-u.ac.jp/class/biomedical/