2022 Fiscal Year Final Research Report
Signaling in NMJ formation and therapeutic intervention against neuromuscular disorders
| Project/Area Number |
20H00496
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Medium-sized Section 48:Biomedical structure and function and related fields
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| 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)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | 神経筋シナプス / シグナル伝達 / 神経科学 |
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| 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.
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| Free Research Field |
分子生物学
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| 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。
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