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Possibility of treatments for amelioration of spinal cord injury -Regulation of extracellular environments and inflammation control

Research Project

Project/Area Number 17K10949
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Orthopaedic surgery
Research InstitutionAichi Medical University

Principal Investigator

Takeuchi Kosei  愛知医科大学, 医学部, 教授 (90206946)

Co-Investigator(Kenkyū-buntansha) 玉田 靖  信州大学, 学術研究院繊維学系, 教授 (70370666)
Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords脊髄損傷 / 神経再生 / コンドロイチン硫酸 / 核酸医薬 / 再生医療 / 細胞外マトリックス / 再生環境制御 / バイオマテリアル / プロテオグリカン / DDS / 再生医学 / 神経科学 / 生体材料 / 移植・再生医療 / 細胞・組織
Outline of Final Research Achievements

Injured adult neurons in the mammalian central nervous system rarely regenerate because some of the intracellular and cell-surface environmental factors inhibit axon regrowth. Chondroitin sulfate (CS) is the most abundant and potent exogenous inhibitor of axonal regeneration. We have showed already that KO mice against CS biosynthesis recovered much faster and more completely than do wild-type mice. We try to establish the accurate inhibition systems of CS-expressions in vivo from the drug screening system, to regulate CS-expressions and modifications in the injury area. We selected the drugs (Antisense oligonucleotide: ASOs) to down-regulate the CS-expressions. The recovery of these mice which treated with drug delivery systems reached the levels of satisfactory amelioration comparable to those of KO mice. Taken together, our results indicated that our screened ASOs delivery system is a promising therapeutic target for treatment of the spinal cord injury and brain infarction.

Academic Significance and Societal Importance of the Research Achievements

脊髄損傷の治療において、再生阻害因子除去および糖鎖発現制御による再生環境整備という観点は新しいものである。とくに研究期間中に発現抑制が可能な核酸医薬を選択し、その機能を検討できたことは治療応用につながるものである(現に、企業主導でのヒト応用を目指した創薬導出に繋がっている)。当初計画していた薬剤デリバリーの機材検討は無くとも効果を発揮すること、炎症における核酸医薬デリバリーの新しい機序を見出した。さらに糖鎖を中心とした解析から、脊髄損傷に対しての全く新しい概念シナプスコネクターの可能性を見出し、これら再生環境整備とシナプス結合を統合した全く新しい展望など当初想定外の発見と結果を示すことが出来た

Report

(5 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (35 results)

All 2021 2020 2019 2018 2017 Other

All Int'l Joint Research (5 results) Journal Article (10 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 10 results,  Open Access: 10 results,  Acknowledgement Compliant: 1 results) Presentation (16 results) (of which Int'l Joint Research: 4 results,  Invited: 3 results) Remarks (1 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] オックスフォード大学(英国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] DZEN(ドイツ神経変性疾患センター)(ドイツ)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] EMBL(ヨーロッパ分子科学連合)/DZNE(ドイツ神経変性センター)/Max Planck Institute(ドイツ)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] EMBL/MaxPlank Institute/Neuroregeneration group(ドイツ)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] EMBL(ドイツ)

    • Related Report
      2017 Research-status Report
  • [Journal Article] A synthetic synaptic organizer protein restores glutamatergic neuronal circuits2020

    • Author(s)
      Suzuki K、Elegheert J、Song I、Sasakura H、Senkov O、Matsuda K、Kakegawa W、Clayton A J、Chang V T、Ferrer-Ferrer M、Miura E、Kaushik R、Ikeno M、Morioka Y、Takeuchi Y、Shimada T、Otsuka S、Stoyanov S、Watanabe M、Takeuchi K、Dityatev A、Aricescu A R、Yuzaki M
    • Journal Title

      Science

      Volume: 369 Issue: 6507 Pages: 1074-1091

    • DOI

      10.1126/science.abb4853

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Chondroitin sulfate N-acetylgalactosyltransferase-1 knockout shows milder phenotype in experimental autoimmune encephalomyelitis than in wild type2020

    • Author(s)
      Inada Rino、Miyamoto Katsuichi、Tanaka Noriko、Moriguchi Kota、Kadomatsu Kenji、Takeuchi Kosei、Igarashi Michihiro、Kusunoki Susumu
    • Journal Title

      Glycobiology

      Volume: 31 Issue: 3 Pages: 260-265

    • DOI

      10.1093/glycob/cwaa072

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Isozyme-Specific Role of SAD-A in Neuronal Migration During Development of Cerebral Cortex2018

    • Author(s)
      Nakanishi Keiko、Niida Hiroyuki、Tabata Hidenori、Ito Tsuyoshi、Hori Yuki、Hattori Madoka、Johmura Yoshikazu、Yamada Chisato、Ueda Takashi、Takeuchi Kosei、Yamada Kenichiro、Nagata Koh-ichi、Wakamatsu Nobuaki、Kishi Masashi、Pan Y Albert、Ugawa Shinya、Shimada Shoichi、Sanes Joshua R、Higashi Yujiro、Nakanishi Makoto
    • Journal Title

      Cerebral Cortex

      Volume: 160 Issue: 9 Pages: 721-721

    • DOI

      10.1093/cercor/bhy253

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Craniofacial abnormality with skeletal dysplasia in mice lacking chondroitin sulfate N-acetylgalactosaminyltransferase-12018

    • Author(s)
      Ida-Yonemochi Hiroko、Morita Wataru、Sugiura Nobuo、Kawakami Ryosuke、Morioka Yuki、Takeuchi Yuka、Sato Toshiya、Shibata Shunichi、Watanabe Hideto、Imamura Takeshi、Igarashi Michihiro、Ohshima Hayato、Takeuchi Kosei
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 17134-17134

    • DOI

      10.1038/s41598-018-35412-5

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Growth cone phosphoproteomics reveals that GAP-43 phosphorylated by JNK is a marker of axon growth and regeneration.2018

    • Author(s)
      Okada M*, Kawasaki A*, Tamada A*, Okuda S, Nozumi M, Ito Y, Kobayashi D, Yamasaki T, Yokoyama R, Shibata T, Nishina H, Yoshida Y, Fujii Y, Takeuchi K, Igarashi M(*These three authorscontributed equally.).
    • Journal Title

      ISCIENCE

      Volume: 4 Pages: 190-203

    • DOI

      10.1016/j.isci.2018.05.019

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Roles of CSGalNAcT1, a key enzyme in regulation of CS synthesis, in neuronal regeneration and plasticity2017

    • Author(s)
      Igarashi M, Takeuchi K, Sugiyama S.
    • Journal Title

      Neurochem Int.

      Volume: 17 Pages: 0197-0186

    • DOI

      10.1016/j.neuint.2017.10.001

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Abnormalities in perineuronal nets and behavior in mice lacking CSGalNAcT1, a key enzyme in chondroitin sulfate synthesis2017

    • Author(s)
      Yoshioka Nozomu、Miyata Shinji、Tamada Atsushi、Watanabe Yumi、Kawasaki Asami、Kitagawa Hiroshi、Takao Keizo、Miyakawa Tsuyoshi、Takeuchi Kosei、Igarashi Michihiro
    • Journal Title

      Mol Brain

      Volume: 10 Issue: 1 Pages: 47-47

    • DOI

      10.1186/s13041-017-0328-5

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chondroitin Sulfate Is Required for Onset and Offset of Critical Period Plasticity in Visual Cortex2017

    • Author(s)
      Hou X, Yoshioka N, Tsukano H, Sakai A, Miyata S, Watanabe Y, Yanagawa Y, Sakimura K, Takeuchi K, Kitagawa H, Hensch TK, Shibuki K, Igarashi M, Sugiyama S
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 12646-12646

    • DOI

      10.1038/s41598-017-04007-x

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Lifespan extension by peroxidase and dual oxidase-mediated ROS signaling through pyrroloquinoline quinone in C. elegans.2017

    • Author(s)
      Sasakura H, Moribe H, Nakano M, Ikemoto K, Takeuchi K,
    • Journal Title

      J Cell Sci.

      Volume: 130 Issue: 15 Pages: 2631-2643

    • DOI

      10.1242/jcs.202119

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extracellular Signals induce Glycoprotein M6a Clustering of Lipid-rafts and associated Signaling Molecules.2017

    • Author(s)
      Honda A, Ito Y, Takahashi-Niki, Matsushita N, Nozumi M, Tabata H, Takeuchi K, Igarashi M
    • Journal Title

      J Neurosci.

      Volume: 37(15) Issue: 15 Pages: 4046-4064

    • DOI

      10.1523/jneurosci.3319-16.2017

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] 脊髄損傷治療に向けての核酸医薬の応用展開 ‐神経再生阻害因子を如何に抑え、再生環境を制御するか‐2021

    • Author(s)
      武内恒成
    • Organizer
      第20回 日本再生医療学会 シンポジウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Rapid and robust recovery from spinal cord injury: cocktail treatment for re-wiring and against repulsion2020

    • Author(s)
      笹倉 寛之;, 鈴木 邦道, 池野 正史, 森岡 幸, 武内 由佳, 柚崎 通介, 武内 恒成
    • Organizer
      第43回 日本神経科学大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Development of hTERT-expanded cell-based regenerative medicine in neurological diseases and spinal cord injury2020

    • Author(s)
      池野 正史, 笹倉 寛之, 武内 恒成
    • Organizer
      第43回 日本神経科学大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] シナプスコネクターCPTXと再生抑制因子コンドロイチン硫酸の操作による脊髄損傷回復2020

    • Author(s)
      笹倉 寛之, 鈴木 邦道, 池野 正史, 森岡 幸, 武内 由佳, 柚崎 通介, 武内 恒成
    • Organizer
      第42回神経組織培養研究会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Development of hTERT-expanded primary cells and cell-based regenerative medicine2020

    • Author(s)
      池野 正史, 鈴木伸卓、笹倉 寛之, 武内 恒成
    • Organizer
      第43回 日本分子生物学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 中枢神経損傷再生回復にむけたシナプスコネクターCPTXと反発因子の操作2020

    • Author(s)
      笹倉 寛之, 鈴木 邦道, 池野 正史, 森岡 幸, 武内 由佳, 柚崎 通介, 武内 恒成
    • Organizer
      第43回 日本分子生物学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 核酸医薬による中枢神経損傷への治療展開ー脊髄損傷治療に向けてのドラッグスクリーニングとその応用ー2019

    • Author(s)
      武内恒成、笹倉寛之、笠原勇矢、小比賀聡
    • Organizer
      日本分子生物学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Neuronal functions with Chondriotin sulfate enhancement by pyroloquinoline quinone and polyphenols.2019

    • Author(s)
      Hiroyuki Sasakura, Kosei Takeuchi
    • Organizer
      日本分子生物学会
    • Related Report
      2019 Research-status Report
  • [Presentation] ヒト初代培養細胞へのTERT遺伝子導入による増殖期間の延長効果2019

    • Author(s)
      池野正史、鈴木伸卓、武内恒成
    • Organizer
      日本分子生物学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Regulation of chondroitin sulfate gene in vivo, to recovery from spinal cord injury and brain infarction2018

    • Author(s)
      Kosei Takeuchi
    • Organizer
      FENS(ヨーロッパ神経化学連合合同学会)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Lifespan extension and ECM remodeling by dual oxidase-mediated ROS signaling.2018

    • Author(s)
      Hiroyuki Sasakura, Hiroki Moribe, Kazuto Ikemoto, Ikue Mori, Kosei Takeuchi
    • Organizer
      日本細胞生物学会
    • Related Report
      2018 Research-status Report
  • [Presentation] In vivo regulation of Chondroitin sulfate gene to recovery from Spinal cord injury and brain infarction2018

    • Author(s)
      武内恒成
    • Organizer
      新学術領域研究合同班会議
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] In vivo における糖鎖発現酵素・コンドロイチン硫酸合成酵素の発現制御による脊髄損傷の機能回復2018

    • Author(s)
      武内恒成
    • Organizer
      日本神経組織培養研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] In vivo regulation of chondroitin sulfate gene to recovery from spinal cord injury and brain infarction2018

    • Author(s)
      Kosei Takeuchi
    • Organizer
      ISN(国際神経学会)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 脊髄損傷修復に向けての核酸医薬治療の可能性2017

    • Author(s)
      武内恒成
    • Organizer
      第2回革新的バイオ研究開発シンポジウム(日本核酸医薬学会)
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] In vivo regulation of chondroitin sulfate gene to recovery from spinal cord injury and brain infarction2017

    • Author(s)
      Kosei Takeuchi
    • Organizer
      ISDN(国際神経発生学会)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Remarks] 愛知医科大学医学部細胞生物学 ホームページ

    • URL

      https://www.take-lab.org/

    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 特願2020-0028792020

    • Inventor(s)
      柚崎通介、鈴木邦道、Radu Aricesu,武内恒成
    • Industrial Property Rights Holder
      柚崎通介、鈴木邦道、Radu Aricesu,武内恒成
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-002879
    • Filing Date
      2020
    • Acquisition Date
      2020
    • Related Report
      2020 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 人工興奮性シナプスコネクタとその脊髄損傷処置への使用2020

    • Inventor(s)
      鈴木邦道、武内恒成、柚崎通介
    • Industrial Property Rights Holder
      鈴木邦道、武内恒成、柚崎通介
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-002879
    • Filing Date
      2020
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] コンドロイチン硫酸生合成を阻害するアンチセンス核酸2017

    • Inventor(s)
      小比賀聡、笠原勇矢、武内恒成
    • Industrial Property Rights Holder
      小比賀聡、笠原勇矢、武内恒成
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Acquisition Date
      2018
    • Related Report
      2018 Research-status Report

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Published: 2017-04-28   Modified: 2022-12-28  

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