Analysis for sensory neural network formation

• Project/Area Number: 18K14840
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46020:Anatomy and histopathology of nervous system-related
• Research Institution: Keio University
• Principal Investigator: Shibata Shinsuke 慶應義塾大学, 医学部(信濃町), 訪問教授 (70407089)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 感覚神経 / 触覚 / 神経回路網 / 神経回路形成 / 発生 / 異痛症 / 神経回路 / 神経堤 / モデルマウス

Outline of Final Research Achievements

In this project, in order to elucidate the tactile neural network formation mechanism on the course of development in mice, we used the multiple genetically modified animals which cause the abnormalities of the tactile sensation. The touch sensation is indispensable for the survival, then we tried to obtain the fundamental data about the process of the tactile circuit formation in vivo. To achieve this purpose, we examined the behavioral abnormality in tactile sensation with some mice strain. The abnormalities of the neural circuits were visualized at the optical microscope level, and the target factors were identified. The abnormal neural network were completely analyzed both with macro-level MRI and with micro-level electron microscope imaging.

Academic Significance and Societal Importance of the Research Achievements

触覚を担うの神経回路網は、外傷などの神経損傷後の回復過程で回路異常をきたすことがあり、異痛症と呼ばれているが、その形成機序は十分に明らかにはなっていなかった。現在でも外傷などに伴って生じる慢性疼痛に苦しむ患者さんは増え続けており、日本では成人人口の２割を超える患者さんが苦しんでいるとも言われている。全世界では１０億人を超える患者さんがいるとの試算もあり、発生学的に触覚や痛覚の回路形成に重要な分子メカニズムを解析することは、このような慢性疼痛の患者さんの疼痛発生機序の理解に役立つ可能性があると考えている。

Research Products

• [Int'l Joint Research] Harvard University/Chicago University/Tufts University(米国)
• [Int'l Joint Research] University College London(英国)
• [Int'l Joint Research] Harvard University/Chicago University(米国)
• [Int'l Joint Research] Harvard University/Chicago University(米国)
• [Journal Article] A robust culture system to generate neural progenitors with gliogenic competence from clinically relevant induced pluripotent stem cells for treatment of spinal cord injury (2020)
  • Author(s): Kamata Yasuhiro、Isoda Miho、Sanosaka Tsukasa、Shibata Reo、Ito Shuhei、Okubo Toshiki、Shinozaki Munehisa、Inoue Mitsuhiro、Koya Ikuko、Shibata Shinsuke、Shindo Tomoko、Matsumoto Morio、Nakamura Masaya、Okano Hideyuki、Nagoshi Narihito、Kohyama Jun
  • Journal Title: STEM CELLS Translational Medicine Volume: 10 Issue: 3 Pages: 398-413
  • DOI: 10.1002/sctm.20-0269
  • Peer Reviewed
• [Journal Article] Regulation of Fetal Genes by Transitions among RNA-Binding Proteins during Liver Development (2020)
  • Author(s): Suzuki Toru、Adachi Shungo、Kikuguchi Chisato、Shibata Shinsuke、Nishijima Saori、Kawamoto Yurie、Iizuka Yusuke、Koseki Haruhiko、Okano Hideyuki、Natsume Tohru、Yamamoto Tadashi
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 23 Pages: 9319-9319
  • DOI: 10.3390/ijms21239319
  • Peer Reviewed / Open Access
• [Journal Article] Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells (2020)
  • Author(s): Kajikawa Keita、Imaizumi Kent、Shinozaki Munehisa、Shibata Shinsuke、Shindo Tomoko、Kitagawa Takahiro、Shibata Reo、Kamata Yasuhiro、Kojima Kota、Nagoshi Narihito、Matsumoto Morio、Nakamura Masaya、Okano Hideyuki
  • Journal Title: Molecular Brain Volume: 13 Issue: 1 Pages: 1-12
  • DOI: 10.1186/s13041-020-00662-w
  • Peer Reviewed / Open Access
• [Journal Article] The liver-brain-gut neural arc maintains the Treg cell niche in the gut (2020)
  • Author(s): Teratani T, Mikami Y, Nakamoto N, Suzuki T, Harada Y, Okabayashi K, Hagihara Y, Taniki N, Kohno K, Sibata S, Miyamoto K, Ishigame H, Chu Po-Sung, Sujino T, Suda W, Hattori M, Matsui M, Okada T, Okano H, Inoue M, Yada T, Kitagawa Y, Yoshimura A, Tanida M, Tsuda M, Iwasaki Y, Kanai T.
  • Journal Title: Nature Volume: 585 Issue: 7826 Pages: 591-596
  • DOI: 10.1038/s41586-020-2425-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Macrophages fine-tune pupil shape during development (2020)
  • Author(s): Takahashi M, Misaki M, Shibata S, Iga T, Shindo T, Tai-Nagara I, Hirata A, Ogawa M, Miyamoto T, Nakagawa T, Ema M, Ichiyama Y, Shima DT, Hozumi K, Nishimura S, Kubota Y
  • Journal Title: Dev Biol Volume: 464 Issue: 2 Pages: 137-144
  • DOI: 10.1016/j.ydbio.2020.06.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sequential Matrix Metalloproteinase-1 Expression Triggered by Infiltrating Monocytic Lineage Cells Modulates Pathophysiological Aspects of Human Nonalcoholic Steatohepatitis</p> (2020)
  • Author(s): Okazaki Isao、Shibata Shinsuke、Ando Wataru、Yanagawa Takayo、Yokomori Hiroaki、Sonoda Akira、Suzuki Norihiko、Yamanouchi Eigoro、Okada Shinya、Kamikura Shinichi、Hachimura Kazuaki、Takaki Takashi、Otori Katsuya、Suzuki Yutaka、Okano Hideyuki、Inagaki Yutaka
  • Journal Title: Metalloproteinases In Medicine Volume: Volume 7 Pages: 1-13
  • DOI: 10.2147/mnm.s252991
  • Peer Reviewed / Open Access
• [Journal Article] Lem2 and Lnp1 maintain the membrane boundary between the nuclear envelope and endoplasmic reticulum (2020)
  • Author(s): Hirano Yasuhiro、Kinugasa Yasuha、Osakada Hiroko、Shindo Tomoko、Kubota Yoshino、Shibata Shinsuke、Haraguchi Tokuko、Hiraoka Yasushi
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 276-276
  • DOI: 10.1038/s42003-020-0999-9
  • Peer Reviewed / Open Access
• [Journal Article] Pathological processes in aqueous humor due to iris atrophy predispose to early corneal graft failure in humans and mice (2020)
  • Author(s): Yamaguchi Takefumi、Higa Kazunari、Yagi-Yaguchi Yukari、Ueda Koji、Noma Hisashi、Shibata Shinsuke、Nagai Toshihiro、Tomida Daisuke、Yasu-Mimura Ririko、Ibrahim Osama、Matoba Ryo、Tsubota Kazuo、Hamrah Pedram、Yamada Jun、Kanekura Kohsuke、Shimazaki Jun
  • Journal Title: Science Advances Volume: 6 Issue: 20 Pages: 5195-5195
  • DOI: 10.1126/sciadv.aaz5195
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology (2020)
  • Author(s): Tanaka Hikari, Tagawa Kazuhiko, Okazawa Hitoshi et al.
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 507-507
  • DOI: 10.1038/s41467-020-14353-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents. (2020)
  • Author(s): Khazaei M, Ahuja CS, Nakashima H, Nagoshi N, Li L, Wang J, Chio J, Badner A, Seligman D, Ichise A, Shibata S, Fehlings MG
  • Journal Title: Sci Transl Med Volume: 12(525) Issue: 525 Pages: 1-14
  • DOI: 10.1126/scitranslmed.aau3538
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Developmental analyses of mouse embryos and adults using a non-overlapping tracing system for all three germ layers (2019)
  • Author(s): Serizawa Takashi、Isotani Ayako、Matsumura Takafumi、Nakanishi Katsuyuki、Nonaka Shigenori、Shibata Shinsuke、Ikawa Masahito、Okano Hideyuki
  • Journal Title: Development Volume: 146 Pages: 1-11
  • DOI: 10.1242/dev.174938
  • NAID: 120006957441
  • Peer Reviewed / Open Access
• [Journal Article] Decreased Activity of the Ghrhr and Gh Promoters Causes Dominantly Inherited GH Deficiency in Humanized GH1 Mouse Models. (2019)
  • Author(s): Daisuke Ariyasu, Emika Kubo, Daisuke Higa, Shinsuke Shibata, Yutaka Takaoka, Michihiko Sugimoto, Kazunori Imaizumi, Tomonobu Hasegawa, Kimi Araki
  • Journal Title: Endocrinology Volume: 160(11) Issue: 11 Pages: 2673-2691
  • DOI: 10.1210/en.2019-00306
  • Peer Reviewed / Open Access
• [Journal Article] The adeno-associated virus rh10 vector is an effective gene transfer system for chronic spinal cord injury. (2019)
  • Author(s): Hoshino Y, Nishide K, Nagoshi N, Shibata S, Moritoki N, Kojima K, Tsuji O, Matsumoto M, Kohyama J, Nakamura M, Okano H.
  • Journal Title: Scientific Reports Volume: 9(1) Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41598-019-46069-z
  • Peer Reviewed / Open Access
• [Journal Article] Large-Area Fluorescence and Electron Microscopic Correlative Imaging With Multibeam Scanning Electron Microscopy. (2019)
  • Author(s): Shibata S, Iseda T, Mitsuhashi T, Oka A, Shindo T, Moritoki N, Nagai T, Otsubo S, Inoue T, Sasaki E, Akazawa C, Takahashi T, Schalek R, Lichtman JW and Okano H.
  • Journal Title: Front. Neural Circuits Volume: 13 Pages: 1-18
  • DOI: 10.3389/fncir.2019.00029
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Human Induced Pluripotent Stem Cell-Derived Tissue Model of a Cerebral Tract Connecting Two Cortical Regions. (2019)
  • Author(s): Kirihara T, Luo Z, Chow SYA, Misawa R, Kawada J, Shibata S, Khoyratee F, Vollette CA, Volz V, Levi T, Fujii T, Ikeuchi Y
  • Journal Title: iScience Volume: 14 Pages: 301-311
  • DOI: 10.1016/j.isci.2019.03.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] シナプスレベルの脳回路研究の最先端 (2018)
  • Author(s): 信藤 知子, 井原 諒, 盛一 伸子, 永井 俊弘, 岡野 栄之, 芝田 晋介
  • Journal Title: 月刊「細胞」特集・シナプス研究の最先端 Volume: 2018年12月号 50(14) Pages: 679-682
• [Presentation] Novel procedure for visualizing specific neural circuit information by using large area correlative light and electron microscopy imaging with multi-beam scanning electron microscopy (2021)
  • Author(s): 芝田 晋介, 井原 諒, 伊勢田 太郎, 信藤 知子, 盛一 伸子, 永井 俊弘, 岡野 栄之
  • Organizer: 第126回 日本解剖学会総会・全国学術集会・第98回 日本生理学会大会
  • Invited
• [Presentation] iPS細胞を用いた末梢神経系の再生戦略 (2021)
  • Author(s): 芝田 晋介, 木村 洋朗, 西島 貴之, 信藤 知子
  • Organizer: 第20回日本再生医療学会総会
  • Invited
• [Presentation] Large area serial section 3D electron microscope imaging with multi-beam scanning electron microscopy for visualizing neural circuit (2020)
  • Author(s): 芝田 晋介, 信藤 知子, 井原 諒, 伊勢田 太郎, 盛一 伸子, 永井 俊弘, 岡野 栄之
  • Organizer: 第125回日本解剖学会総会・全国学術集会
  • Invited
• [Presentation] Large area correlative light and electron microscopy imaging with multi-beam scanning electron microscopy for visualizing specific neural circuit (2019)
  • Author(s): 芝田 晋介, 信藤 知子, 井原 諒, 伊勢田 太郎, 盛一 伸子, 永井 俊弘, 岡野 栄之
  • Organizer: NEURO2019第42回日本神経科学大会・第62回日本神経化学会大会
• [Presentation] LA-CLEM: novel procedure for Large area Correlative Light and Electron Microscopy analysis with multi-beam scanning electron microscopy (2018)
  • Author(s): 伊勢田太郎, 芝田 晋介, 三橋隆行, 大坪進矢, 信藤知子, 高橋孝雄, 岡野栄之
  • Organizer: 第40回日本生物学的精神医学会, 第61回日本神経化学会大会 合同年会
• [Presentation] Localization of Alzheimer's disease early phase marker, phospho-M ARCKS (Ser46) at electron microscopic level (2018)
  • Author(s): 一瀬綾花, 岡野栄之, 芝田 晋介, 岡澤均, 藤田慶大
  • Organizer: 第41回日本神経科学大会
• [Patent(Industrial Property Rights)] 電子顕微鏡用試料の作成システム、電子顕微鏡用試料の作成方法およびこれに用いられるプラズマ処理装置、スパッタ装置、テープ搬送機構 (2018)
  • Inventor(s): 芝田晋介, 信藤知子, 岡野栄之, 後藤修一
  • Industrial Property Rights Holder: 芝田晋介, 信藤知子, 岡野栄之, 後藤修一
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-248067
  • Filing Date: 2018