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Understanding of the mechanism of ribitol-phosphate modification and application of its physiological function to therapy

Research Project

Project/Area Number 18H02616
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionEhime University (2020)
Kobe University (2018-2019)

Principal Investigator

Kanagawa Motoi  愛媛大学, 医学系研究科, 教授 (00448044)

Co-Investigator(Kenkyū-buntansha) 萬谷 博  地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究副部長 (20321870)
田村 純一  鳥取大学, 農学部, 教授 (30221401)
片野坂 友紀  岡山大学, 医歯薬学総合研究科, 講師 (60432639)
山口 芳樹  東北医科薬科大学, 薬学部, 教授 (90323451)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Keywords糖鎖 / 筋ジストロフィー / 疾患モデル / ジストログリカン / リビトールリン酸 / フクチン
Outline of Final Research Achievements

Ribitol-phosphate is a novel post-translational moiety that we identified and its abnormal modification results in muscular dystrophy and mental retardation. However, it was unknown how defects in ribitol-phosphate modification lead to tissue dysfunction and human diseases. In this study, using ribitol-phosphate-deficient mice we showed that the degree of ribitol-phosphate modification during fetal stage is related to pathological severity in brain and that ribitol-phosphate modification plays important roles in function of cardiac muscle cells and the maintenance of cytoskeletons. Based on these findings, we proposed therapeutic strategies to muscular dystrophy.

Academic Significance and Societal Importance of the Research Achievements

リビトールリン酸修飾異常症の病態分子機構に不明な点は多く、有効な治療法も存在しない。本研究では、作出したリビトールリン酸不全マウスの病態解析をすすめ、リビトールリン酸修飾の不全から病的表現型に至る発症メカニズムを解明できた。更に、発症メカニズムに基づいた治療戦略の提唱にも至った。これらの成果は、疾患機序の解明や治療法の開発につながり、学術的・社会的にも大きな貢献を果たした。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (29 results)

All 2020 2019 2018 Other

All Journal Article (13 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 13 results,  Open Access: 13 results) Presentation (10 results) (of which Int'l Joint Research: 2 results,  Invited: 9 results) Remarks (4 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] Congenital hearing impairment associated with peripheral cochlear nerve dysmyelination in glycosylation-deficient muscular dystrophy2020

    • Author(s)
      Morioka Shigefumi、Sakaguchi Hirofumi、Mohri Hiroaki、Taniguchi-Ikeda Mariko、Kanagawa Motoi、Suzuki Toshiaki、Miyagoe-Suzuki Yuko、Toda Tatsushi、Saito Naoaki、Ueyama Takehiko
    • Journal Title

      PLOS Genetics

      Volume: 16 Issue: 5 Pages: 1-28

    • DOI

      10.1371/journal.pgen.1008826

    • NAID

      120006863578

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lactone-Driven Ester-to-Amide Derivatization for Sialic Acid Linkage-Specific Alkylamidation2020

    • Author(s)
      Jun-Ichi Furukawa 1, Hisatoshi Hanamatsu 2, Takashi Nishikaze 3, Hiroshi Manya 4, Nobuaki Miura 5, Hirokazu Yagi 6, Ikuko Yokota 1, Keiko Akasaka-Manya 4, Tamao Endo 4, Motoi Kanagawa 7 8, Norimasa Iwasaki 1, Koichi Tanaka 3
    • Journal Title

      Anal Chem .

      Volume: 3 Issue: 21 Pages: 14383-14392

    • DOI

      10.1021/acs.analchem.0c02209

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Crystal structures of fukutin-related protein (FKRP), a ribitol-phosphate transferase related to muscular dystrophy.2020

    • Author(s)
      Kuwabara N, Imae R, Manya H, Tanaka T, Mizuno M, Tsumoto H, Kanagawa M, Kobayashi K, Toda T, Senda T, Endo T, Kato R.
    • Journal Title

      Nat Commun.

      Volume: 11 Issue: 1 Pages: 303-303

    • DOI

      10.1038/s41467-019-14220-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure2019

    • Author(s)
      Ujihara Yoshihiro、Kanagawa Motoi、Mohri Satoshi、Takatsu Satomi、Kobayashi Kazuhiro、Toda Tatsushi、Naruse Keiji、Katanosaka Yuki
    • Journal Title

      Nature Communications

      Volume: 10 Issue: 1 Pages: 5754-5754

    • DOI

      10.1038/s41467-019-13623-2

    • NAID

      120006777089

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characterization of dystroglycan binding in adhesion of human induced pluripotent stem cells to laminin-511 E8 fragment2019

    • Author(s)
      Sugawara Yumika、Hamada Keisuke、Yamada Yuji、Kumai Jun、Kanagawa Motoi、Kobayashi Kazuhiro、Toda Tatsushi、Negishi Yoichi、Katagiri Fumihiko、Hozumi Kentaro、Nomizu Motoyoshi、Kikkawa Yamato
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 1-12

    • DOI

      10.1038/s41598-019-49669-x

    • NAID

      120006728095

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Myo-Glyco disease Biology: Genetic Myopathies Caused by Abnormal Glycan Synthesis and Degradation2019

    • Author(s)
      Kanagawa Motoi
    • Journal Title

      Journal of Neuromuscular Diseases

      Volume: - Issue: 2 Pages: 1-13

    • DOI

      10.3233/jnd-180369

    • NAID

      120006888540

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation2019

    • Author(s)
      Sekiya Hiroaki、Kowa Hisatomo、Koga Hinako、Takata Mariko、Satake Wataru、Futamura Naonobu、Funakawa Itaru、Jinnai Kenji、Takahashi Motonori、Kondo Takeshi、Ueno Yasuhiro、Kanagawa Motoi、Kobayashi Kazuhiro、Toda Tatsushi
    • Journal Title

      Acta Neuropathologica

      Volume: 137 Issue: 3 Pages: 455-466

    • DOI

      10.1007/s00401-019-01961-w

    • NAID

      120006599160

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transsynaptic Binding of Orphan Receptor GPR179 to Dystroglycan-Pikachurin Complex Is Essential for the Synaptic Organization of Photoreceptors2018

    • Author(s)
      Orlandi Cesare、Omori Yoshihiro、Wang Yuchen、Cao Yan、Ueno Akiko、Roux Michel J.、Condomitti Giuseppe、de Wit Joris、Kanagawa Motoi、Furukawa Takahisa、Martemyanov Kirill A.
    • Journal Title

      Cell Reports

      Volume: 25 Issue: 1 Pages: 130-145

    • DOI

      10.1016/j.celrep.2018.08.068

    • NAID

      120006531168

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] In silico drug screening by using genome-wide association study data repurposed dabrafenib, an anti-melanoma drug, for Parkinson’s disease2018

    • Author(s)
      Uenaka Takeshi、Satake Wataru、Cha Pei-Chieng、Hayakawa Hideki、Baba Kousuke、Jiang Shiying、Kobayashi Kazuhiro、Kanagawa Motoi、Okada Yukinori、Mochizuki Hideki、Toda Tatsushi
    • Journal Title

      Human Molecular Genetics

      Volume: 27 Pages: 3974-3985

    • DOI

      10.1093/hmg/ddy279

    • NAID

      120006549191

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CDP-glycerol inhibits the synthesis of the functionalO-mannosyl glycan of α-dystroglycan2018

    • Author(s)
      Imae Rieko、Manya Hiroshi、Tsumoto Hiroki、Osumi Kenji、Tanaka Tomohiro、Mizuno Mamoru、Kanagawa Motoi、Kobayashi Kazuhiro、Toda Tatsushi、Endo Tamao
    • Journal Title

      Journal of Biological Chemistry

      Volume: 293 Issue: 31 Pages: 12186-12198

    • DOI

      10.1074/jbc.ra118.003197

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cell surface flip-flop of phosphatidylserine is critical for PIEZO1-mediated myotube formation2018

    • Author(s)
      Tsuchiya Masaki、Hara Yuji、Okuda Masaki、Itoh Karin、Nishioka Ryotaro、Shiomi Akifumi、Nagao Kohjiro、Mori Masayuki、Mori Yasuo、Ikenouchi Junichi、Suzuki Ryo、Tanaka Motomu、Ohwada Tomohiko、Aoki Junken、Kanagawa Motoi、Toda Tatsushi、Nagata Yosuke、Matsuda Ryoichi、Takayama Yasunori、Tominaga Makoto、Umeda Masato
    • Journal Title

      Nature Communications

      Volume: 9 Issue: 1 Pages: 2049-2049

    • DOI

      10.1038/s41467-018-04436-w

    • NAID

      120006471161

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ribitol-phosphate-a newly identified posttranslational glycosylation unit in mammals: structure, modification enzymes and relationship to human diseases2018

    • Author(s)
      Kanagawa Motoi、Toda Tatsushi
    • Journal Title

      The Journal of Biochemistry

      Volume: 163 Issue: 5 Pages: 359-369

    • DOI

      10.1093/jb/mvy020

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Temporal requirement of dystroglycan glycosylation during brain development and rescue of severe cortical dysplasia via gene delivery in the fetal stage2018

    • Author(s)
      Sudo Atsushi、Kanagawa Motoi、Kondo Mai、Ito Chiyomi、Kobayashi Kazuhiro、Endo Mitsuharu、Minami Yasuhiro、Aiba Atsu、Toda Tatsushi
    • Journal Title

      Human molecular genetics

      Volume: 27 Issue: 7 Pages: 1174-1185

    • DOI

      10.1093/hmg/ddy032

    • NAID

      120006459805

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 福山型筋ジストロフィーのモデルマウスを用いた病態解明と治療戦略の開発2020

    • Author(s)
      金川基,戸田達史
    • Organizer
      第38回日本神経治療学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ジストログリカンが担う基底膜―細胞膜連携の破綻と筋ジストロフィー2020

    • Author(s)
      金川基
    • Organizer
      第93回日本生化学会大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ジストログリカン糖鎖異常を原因とする心筋症の病態機序2020

    • Author(s)
      金川基,氏原嘉洋,片野坂友紀
    • Organizer
      第39回日本糖質学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 新規翻訳後修飾体リビトールリン酸の修飾機序と筋組織における生理的役割2019

    • Author(s)
      金川基
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ジストログリカンの機能発現に必要なリビトールリン酸修飾ゾーンの探索と意義2019

    • Author(s)
      金川基
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 機械負荷に対する防御装置としての糖鎖と機械生物学的な意義2019

    • Author(s)
      金川基
    • Organizer
      第57回日本生物物理学会年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Temporal requirement of dystroglycan glycosylation during brain development and rescue of severe cortical dysplasia via gene delivery in the fetal stage.2019

    • Author(s)
      Kanagawa M, Toda T
    • Organizer
      The 6th International Workshop for Glycosylation Defects in Muscular Dystrophies
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ジストログリカンがつくる基底膜ジャンクションと病態2018

    • Author(s)
      金川 基
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ジストログリカンから見出された新規リビトールリン酸修飾の分子機構と生理機能2018

    • Author(s)
      金川 基
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Pathological analysis of model mice for Fukuyama congenital muscular dystrophy and exploration of therapeutic strategy.2018

    • Author(s)
      Kanagawa M, Fukada SI, Okada T, Takeda SI, Toda T
    • Organizer
      11th Japanese-French Workshop New insights in personalized medicine for neuromuscular diseases: from basic to applied myology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] 愛媛大学大学院医学系研究科 医化学・細胞生物学講座

    • URL

      https://www.m.ehime-u.ac.jp/school/biochem1/

    • Related Report
      2020 Annual Research Report
  • [Remarks] 研究成果のプレスリリース

    • URL

      https://www.kobe-u.ac.jp/research_at_kobe/NEWS/news/2019_12_17_01.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] 研究室ホームページ

    • URL

      http://www.med.kobe-u.ac.jp/clgene/index.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] 神戸大学医学研究科分子脳科学

    • URL

      http://www.med.kobe-u.ac.jp/clgene/index.html

    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 新規CDP-リビトール誘導体2020

    • Inventor(s)
      金川基、徳岡秀紀、戸田達史
    • Industrial Property Rights Holder
      金川基、徳岡秀紀、戸田達史
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-067017
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 筋ジストロフィー関連心筋症の治療又は予防剤2018

    • Inventor(s)
      片野坂友紀, 成瀬恵治, 氏原嘉洋, 戸田達史, 金川基
    • Industrial Property Rights Holder
      片野坂友紀, 成瀬恵治, 氏原嘉洋, 戸田達史, 金川基
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-044752
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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