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Investigation of molecular pathogenesis and development of therapeutic methods for Fukuyama muscular dystrophy and related diseases

Research Project

Project/Area Number 16H05353
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionKobe University

Principal Investigator

Kobayashi Kazuhiro  神戸大学, 医学研究科, 准教授 (90324780)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2019: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2016: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Keywords糖鎖 / 筋ジストロフィー / 脳神経疾患 / 酵素 / 遺伝子 / ジストログリカノパチー / fukutin / α-dystroglycan
Outline of Final Research Achievements

In this study, we aimed to delineate the full O-Man glycan structure of a-dystroglycan (a-DG) whose abnormalities cause muscular dystrophy, to clarify the biosynthesis pathway of the glycan, to understand the pathogenesis of neuronal dysfunction of the disease, and to explore its therapeutic possibility. We determined the unknown glycan structure that contained ribitol phosphate. We also identified the functions of four gene proteins such as fukutin that are responsible for muscular dystrophy, and determined the biosynthesis pathway for ribitol phosphate of the glycan. We could not find novel proteins modified with the O-Man glycan or a-DG ligands. Some therapeutic strategies were found to be effective for the disease model cells and mice. Further investigations are required.

Academic Significance and Societal Importance of the Research Achievements

α-DGのO-Man型糖鎖の完全構造と生合成機構を明らかにしたことで、重篤なα-DGpathyの発症機序を理解でき、新たな治療標的発見、有効な治療法開発につながる。新たな翻訳後修飾の発見であり、医学的のみならず生物学的にも学術的な意義がある。また、O-Man型糖鎖と脳奇形・神経機能との関連を示し、神経機能障害の治療の有効性が示されれば、問題の多い胎児治療ではなく、生後の治療が可能になり、実現可能な脳の治療法の構築につながることが期待でき、社会的意義が大きい。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (31 results)

All 2020 2019 2018 2017 2016 Other

All Int'l Joint Research (2 results) Journal Article (18 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 18 results,  Open Access: 17 results,  Acknowledgement Compliant: 3 results) Presentation (10 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Remarks (1 results)

  • [Int'l Joint Research] Peking University First Hospital(中国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Peking University First Hospital(中国)

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Galectin 3?binding protein suppresses amyloid-β production by modulating β-cleavage of amyloid precursor protein2020

    • Author(s)
      Seki Tsuneyoshi、Kanagawa Motoi、Kobayashi Kazuhiro、Kowa Hisatomo、Yahata Naoki、Maruyama Kei、Iwata Nobuhisa、Inoue Haruhisa、Toda Tatsushi
    • Journal Title

      Journal of Biological Chemistry

      Volume: 295 Issue: 11 Pages: 3678-3691

    • DOI

      10.1074/jbc.ra119.008703

    • Related Report
      2019 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] Psychosocial Twin Cohort Studies in Japan: The Keio Twin Research Center (KoTReC)2019

    • Author(s)
      Ando, J., Fujisawa, K. K., Hiraishi, K.,et al.
    • Journal Title

      Twin Research and Human Genetics

      Volume: 22 Issue: 6 Pages: 591

    • DOI

      10.1017/thg.2019.109

    • NAID

      120007166905

    • URL

      https://pure.teikyo.jp/en/publications/97b4db4d-529e-44b5-b219-7ec0a394029d

    • 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] Triglyceride deposit cardiomyovasculopathy: a rare cardiovascular disorder2019

    • Author(s)
      Li Ming、on behalf of the Japan TGCV study group、Hirano Ken-ichi、Ikeda Yoshihiko、Shimada Kazunori、et al.
    • Journal Title

      Orphanet Journal of Rare Diseases

      Volume: 14 Issue: 1 Pages: 134-134

    • DOI

      10.1186/s13023-019-1087-4

    • Related Report
      2019 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
      2019 Annual Research 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
  • [Journal Article] Cell endogenous activities of fukutin and FKRP coexist with the ribitol xylosyltransferase, TMEM5.2018

    • Author(s)
      Nishihara, R., Kobayashi, K., Imae, R., Tsumoto, H., Manya, H., Mizuno, M., Kanagawa, M., Endo, T., and Toda, T.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 497 Issue: 4 Pages: 1025-1030

    • DOI

      10.1016/j.bbrc.2018.02.162

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [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] 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] Newly developed selective immunoinactivation assay revealed reduction in adipose triglyceride lipase activity in peripheral leucocytes from patients with idiopathic triglyceride deposit cardiomyovasculopathy2018

    • Author(s)
      Takagi Atsuko、Ikeda Yasuyuki、Kobayashi Kunihisa、Kobayashi Kazuhiro、Ikeda Yoshihiko、Kozawa Junji、Miyauchi Hideyuki、Li Ming、Hashimoto Chikako、Hara Yasuhiro、Yamaguchi Satoshi、Suzuki Akira、Toda Tatsushi、Nagasaka Hironori、Hirano Ken-ichi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 495 Issue: 1 Pages: 646-651

    • DOI

      10.1016/j.bbrc.2017.11.070

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel FKRP mutations in a Japanese MDC1C sibship clinically diagnosed with Fukuyama congenital muscular dystrophy2017

    • Author(s)
      Yoshioka Mieko、Kobayashi Kazuhiro、Toda Tatsushi
    • Journal Title

      Brain and Development

      Volume: 39 Issue: 10 Pages: 869-872

    • DOI

      10.1016/j.braindev.2017.05.013

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Deep-intronic variant of fukutin is the most prevalent point mutation of Fukuyama congenital muscular dystrophy in Japan2017

    • Author(s)
      Kobayashi Kazuhiro、Kato Reiko、Kondo-Iida Eri、Taniguchi-Ikeda Mariko、Osawa Makiko、Saito Kayoko、Toda Tatsushi
    • Journal Title

      Journal of Human Genetics

      Volume: 62 Issue: 11 Pages: 945-948

    • DOI

      10.1038/jhg.2017.71

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of a post-translational modification with ribitol-phosphate and its defect in muscular dystrophy2016

    • Author(s)
      Kanagawa M, Kobayashi K, Tajiri M, Manya H, Kuga A, Yamaguchi Y, Akasaka-Manya K, Furukawa J, Mizuno M, Kawakami H, Shinohara Y, Wada Y, Endo T, Toda T.
    • Journal Title

      Cell Reports

      Volume: 14 Issue: 9 Pages: 2209-2223

    • DOI

      10.1016/j.celrep.2016.02.017

    • NAID

      120005728438

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Analysis of phenotype, enzyme activity, and genotype of Chinese patients with POMT1 mutation2016

    • Author(s)
      Haipo Yang, Hiroshi Manya, Kazuhiro Kobayashi, HUI JIAO, Xiaona Fu, Jiangxi Xiao, Xiaoqing Li, Jingmin wang, Yuwu Jiang, TATSUSHI TODA, Tamao Endo, Xiru Wu,Hui Xiong,
    • Journal Title

      J. Hum. Genet

      Volume: 印刷中 Issue: 8 Pages: 753-759

    • DOI

      10.1038/jhg.2016.42

    • NAID

      40020923851

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of α-dystroglycan.2016

    • Author(s)
      Kuwabara N, Manya H, Yamada T, Tateno H, Kanagawa M, Kobayashi K, Akasaka-Manya K, Hirose Y, Mizuno M, Ikeguchi M, Toda T, Hirabayashi J, Senda T, Endo T, Kato R.
    • Journal Title

      Proc Natl Acad Sci U S A.

      Volume: 113 Issue: 33 Pages: 9280-9285

    • DOI

      10.1073/pnas.1525545113

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The muscular dystrophy gene TMEM5encodes a ribitol β1-4 Xylosyltransferase required for the functional glycosylation of dystroglycan.2016

    • Author(s)
      Manya, H., Yamaguchi, Y., Kanagawa, M., Kobayashi, K., Tajiri, M., Akasaka-Manya, K., Kawakami, H., Mizuno, M., Wada, Y., Toda, T., and Endo, T.
    • Journal Title

      J. Biol. Chem

      Volume: 291 Issue: 47 Pages: 24618-24627

    • DOI

      10.1074/jbc.m116.751917

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Wide distribution of alpha-synuclein oligomers in MSA brain detected by proximity ligation2019

    • Author(s)
      関谷博顕, 古和久朋, 古閑日奈子, 髙田真利子, 佐竹渉, 二村直伸, 舟川格, 陣内研二, 高橋玄倫, 近藤武史, 上野易弘, 金川基, 小林千浩, 戸田達史
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Galectin 3 binding proteinはBACE1活性しAβ産生を抑制する2019

    • Author(s)
      関恒慶, 金川基, 小林千浩, 古和久朋, 八幡直樹, 丸山敬, 岩田修永, 井上治久, 戸田達史
    • Organizer
      第38回日本認知症学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Galectin 3 binding proteinは内在性のβ-セクレターゼ活性を制御することでAβ産生を抑制する2019

    • Author(s)
      関恒慶, 金川基, 小林千浩, 古和久朋, 八幡直樹, 丸山敬, 岩田修永, 井上治久, 戸田達史
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] LARGE Gene Therapy for α-Dystroglycanopathies2018

    • Author(s)
      Yoshihisa Ohtsuka, Motoi Kanagawa, Tomoko Chiyo, Kazuhiro Kobayashi, Takashi Okada, Shin’ichi Takeda, Tatsushi Toda
    • Organizer
      11th Japanese-French Workshop
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ジストログリカノパチ-モデルマウスの中枢神経病態の解析2018

    • Author(s)
      首藤篤史、金川基、近藤舞、伊藤千代美、小林千浩、遠藤光晴、南康博 、饗場篤、戸田達史
    • Organizer
      第37回日本糖質学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ジストログリカン異常症の原因となるリビトールリン酸タンデム構造とその生合成機構2017

    • Author(s)
      小林 千浩、金川 基、田尻 道子、萬谷 博、久我 敦、山口 芳樹、和田 芳直、遠藤 玉夫、戸田 達史
    • Organizer
      日本人類遺伝学会第62回大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ジストログリカン異常症の原因となるリビトールリン酸タンデム構造とその生合成経路2017

    • Author(s)
      小林 千浩
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] A de novo mutation of the MYH7 gene in a large Chinese family with autosomal dominant myopathy2016

    • Author(s)
      Kazuhiro Kobayashi, Tetsuya Oda, Hui Xiong, Wataru Satake, Tatsushi Toda
    • Organizer
      The 13th International Congress of Human Genetics
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] αジストログリカン糖鎖のリビトールリン酸タンデム構造とその生合成経路2016

    • Author(s)
      Kazuhiro Kobayashi, Motoi Kanagawa, Michiko Tajiri, Hiroshi Manya, Atsushi Kuga, Yoshiki Yamaguchi, Keiko Akasaka-Manya, Jun-ichi Furukawa, Mamoru Mizuno, Hiroko Kawakami, Yasuro Shinohara, Yoshinao Wada, Tamao Endo, Tatsushi Toda
    • Organizer
      第2回日本筋学会学術集会
    • Related Report
      2016 Annual Research Report
  • [Presentation] αジストログリカン糖鎖のリビトールリン酸タンデム構造とその生合成機構2016

    • Author(s)
      Kazuhiro Kobayashi, Motoi Kanagawa, Michiko Tajiri, Hiroshi Manya, Atsushi Kuga, Yoshiki Yamaguchi, Keiko Akasaka-Manya, Jun-ichi Furukawa, Mamoru Mizuno, Hiroko Kawakami, Yasuro Shinohara, Yoshinao Wada, Tamao Endo, Tatsushi Toda
    • Organizer
      第39回日本分子生物学会年会
    • Related Report
      2016 Annual Research Report
  • [Remarks] 神戸大学大学院医学研究科分子脳科学分野ホームページ

    • URL

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

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report 2017 Annual Research Report 2016 Annual Research Report

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Published: 2016-04-21   Modified: 2021-02-19  

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