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Signaling in NMJ formation and therapeutic intervention against neuromuscular disorders

Research Project

Project/Area Number 20H00496
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 48:Biomedical structure and function and related fields
Research InstitutionThe University of Tokyo

Principal Investigator

Yamanashi Yuji  東京大学, 医科学研究所, 教授 (40202387)

Co-Investigator(Kenkyū-buntansha) 江口 貴大  東京大学, 医科学研究所, 助教 (60845056)
荒川 正行  公益財団法人微生物化学研究会, 微生物化学研究所, 研究員 (90398868)
植田 亮  東京大学, 医科学研究所, 助教 (10445025)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥45,240,000 (Direct Cost: ¥34,800,000、Indirect Cost: ¥10,440,000)
Fiscal Year 2022: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000)
Fiscal Year 2021: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
Fiscal Year 2020: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000)
Keywords神経筋シナプス / シグナル伝達 / 神経科学 / 神経筋疾患 / 神経筋シナプス形成シグナル
Outline of Research at the Start

神経筋シナプス(NMJ)は骨格筋収縮の制御に必須であり、その喪失は呼吸を含む運動機能の喪失を招く。代表者は細胞内分子であるDok-7がNMJ形成シグナルに必須であり、その異常がNMJ形成不全(DOK7型筋無力症)の原因であることを発見した。本研究では、種々のNMJ形成制御因子や化合物を用いたNMJ形成シグナルの解析を進め、より広範な視点から個体の運動機能に必須のNMJ形成シグナルを理解すると共に、多様な神経筋疾患の病態解明と治療基盤の確立を推進する。

Outline of Final Research Achievements

We previously demonstrated that the activation of the muscle-specific receptor kinase MuSK by its essential, cytoplasmic activator Dok-7 is required for NMJ formation and maintenance, and that mutations in the human DOK7 gene underlie NMJ synaptopathy (DOK7 myasthenia). Moreover, we developed the novel therapeutic approach, DOK7 gene therapy, that enhances not only the formation/maintenance but also the reinnervation/regeneration of NMJs in mice. In this study, we aimed to understand molecular mechanisms underlying NMJ formation/maintenance/regeneration and pathophysiological significance of NMJ defects associated with muscle weakness and motor dysfunction, including sarcopenia. Indeed, we successfully identified some protein-phosphorylation signals and calcium-related signals that are important for NMJ formation and maintenance and for motor activity. Also, we advance basic research on another modality of NMJ-targeting therapeutics.

Academic Significance and Societal Importance of the Research Achievements

上記の「研究成果の概要」で述べた通り、我々は神経筋シナプス(NMJ)形成を増強する遺伝子治療の有効性を多様な疾患・病態モデルマウスにおいて確立してきた。その際、加齢変容によるNMJからの運動神経脱離に対し、当該治療が運動神経の再結合、つまりNMJの再生を促すことを発見した。それ故、本研究の成果には、生理的なNMJ形成・維持機構と人為的なNMJ形成増強技術の両者を統合的に理解することで、より広範な視点から、我々の呼吸を含む運動機能制御に必須のNMJを理解すると共に、加齢性の筋力低下を含む多様な神経筋疾患の克服に資するNMJ形成・再生増強技術を開発する点において、高度の学術的、社会的意義を有する。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Comments on the Screening Results   Annual Research Report
  • Research Products

    (14 results)

All 2022 2021 2020 Other

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 1 results) Presentation (7 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Remarks (1 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 2 results)

  • [Journal Article] Adeno-associated virus-mediated expression of an inactive CaMKIIβ mutant enhances muscle mass and strength in mice2022

    • Author(s)
      Eguchi Takahiro、Yamanashi Yuji
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 589 Pages: 192-196

    • DOI

      10.1016/j.bbrc.2021.12.027

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 特集 新組織学シリーズⅡ:骨格筋-今後の研究の発展に向けて Ⅱ.骨格筋組織を支える細胞の役割・応答 神経筋接合部(NMJ)の形成・維持メカニズム-NMJを標的とした治療技術の開発を目指して2021

    • Author(s)
      江口 貴大、山梨 裕司
    • Journal Title

      生体の科学

      Volume: 72 Issue: 6 Pages: 527-531

    • DOI

      10.11477/mf.2425201435

    • ISSN
      0370-9531, 1883-5503
    • Year and Date
      2021-12-15
    • Related Report
      2021 Annual Research Report
  • [Journal Article] DOK7 Gene Therapy Enhances Neuromuscular Junction Innervation and Motor Function in Aged Mice2020

    • Author(s)
      Ueta R, Sugita S, Minegishi Y, Shimotoyodome A, Ota N, Ogiso N, Eguchi T, Yamanashi Y
    • Journal Title

      iScience

      Volume: 23 Issue: 8 Pages: 101385-101385

    • DOI

      10.1016/j.isci.2020.101385

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of salbutamol on neuromuscular junction function and structure in a mouse model of DOK7 congenital myasthenia2020

    • Author(s)
      Webster RG, Vanhaesebrouck AE, Maxwell SE, Cossins JA, Liu W, Ueta R, Yamanashi Y, Beeson DMW
    • Journal Title

      Hum. Mol. Genet.

      Volume: 29 Issue: 14 Pages: 2325-2336

    • DOI

      10.1093/hmg/ddaa116

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] 神経筋接合部を標的とする筋疾患の新規治療法の開発2022

    • Author(s)
      山梨裕司
    • Organizer
      第63回日本神経学会学術集会(シンポジウム S-03-2)
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] CDK5活性化因子p35を起点とした神経筋シナプス形成・維持制御メカニズムの解析2022

    • Author(s)
      江口貴大、依田実朗、山梨裕司
    • Organizer
      第8回日本筋学会学術集会(ポスター発表)
    • Related Report
      2022 Annual Research Report
  • [Presentation] 骨格筋における変異型CaMKIIβの強制発現は筋肥大を誘導する2021

    • Author(s)
      江口貴大、范文蘭、山梨裕司
    • Organizer
      第7回 日本筋学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] A study of therapeutic interventions aimed at enhancing neuromuscular junction innervation and skeletal muscle mass2021

    • Author(s)
      江口貴大、范文蘭、山梨裕司
    • Organizer
      The 16th International Symposium of the Institute Network for Biomedical Sciences
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 神経筋シナプス(NMJ)形成シグナルとNMJ標的治療2020

    • Author(s)
      山梨裕司
    • Organizer
      第6回 日本筋学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 神経筋接合部(NMJ)の形成増強治療は老齢マウスにおけるNMJの神経結合を増強し、運動機能と筋力を強化する2020

    • Author(s)
      江口貴大、杉田聡、峯岸慶彦、下豊留玲、太田宣康、小木曽昇、植田亮、山梨裕司
    • Organizer
      第6回 日本筋学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] DOK7発現ベクターの投与は老齢マウスのNMJにおける神経結合を増強し、運動機能と筋力を強化する2020

    • Author(s)
      江口貴大、杉田聡、峯岸慶彦、下豊留玲、太田宣康、小木曽昇、植田亮、山梨裕司
    • Organizer
      第43回 日本分子生物学会年会
    • Related Report
      2020 Annual Research Report
  • [Remarks] 東京大学医科学研究所腫瘍抑制分野ホームページ

    • URL

      https://www.ims.u-tokyo.ac.jp/genetics/html/home.html

    • Related Report
      2022 Annual Research Report
  • [Patent(Industrial Property Rights)] Methods and Compositions for Treatment of Age-Related Dysfunction2021

    • Inventor(s)
      山梨 裕司、植田 亮、杉田 聡、峯岸 慶彦
    • Industrial Property Rights Holder
      国立大学法人東京大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] Methods and Compositions for Treatment of Age-Related Dysfunction2020

    • Inventor(s)
      山梨 裕司、植田 亮、杉田 聡、峯岸 慶彦
    • Industrial Property Rights Holder
      国立大学法人東京大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
    • Overseas

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Published: 2020-04-28   Modified: 2024-01-30  

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