Molecular signaling in neuromuscular synaptogenesis and myasthenia
| Project/Area Number |
23249013
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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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| Research Field |
General medical chemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
TEZUKA Tohru 東京大学, 医科学研究所, 助教 (50312319)
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| Co-Investigator(Renkei-kenkyūsha) |
NUREKI Osamu 東京大学, 理学系研究科, 教授 (10272460)
NATSUME Tohru 産業技術総合研究所, 創薬分子プロファイリング研究センター, センター長 (00357683)
TAKEDA Shin'ICHI 国立精神, 神経医療研究センター・神経研究所, 部長 (90171644)
MOTOMURA Masakatsu 長崎総合科学大学, 工学部, 教授 (70244093)
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| Project Period (FY) |
2011-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥48,360,000 (Direct Cost: ¥37,200,000、Indirect Cost: ¥11,160,000)
Fiscal Year 2013: ¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000)
Fiscal Year 2012: ¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000)
Fiscal Year 2011: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
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| Keywords | 細胞内シグナル伝達 / 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 revealed that the cytoplasmic adaptor-like protein Dok-7 activates muscle-specific receptor tyrosine kinase MuSK, which is required for neuromuscular synaptogenesis and maintenance. To understand molecular signaling involved in neuromuscular synaptogenesis and myasthenia, we not only studied Dok-7 and MuSK-mediated signaling but also other signaling pathways in skeletal muscle. Our findings revealed that the chaperon protein Mesdc2 plays an important role in cell-surface expression of MuSK’s co-receptor Lrp4, which is essential for NMJ formation and maintenance. Also, we found that the MuSK activator agrin has a separate role in postnatal maintenance of NMJ. Furthermore, we developed an adeno-associated viral vector (AAV-D7), which expresses Dok-7, and showed that AAV-D7 treatment enlarged NMJs and restored motor activities of DOK7 myasthenia model mice, resulting in enhancement of their survival.
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Report
(4 results)
Research Products
(14 results)
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[Journal Article] DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction2014
Author(s)
Sumimasa Arimura, Takashi Okada, Tohru Tezuka, Tomoko Chiyo, Yuko Kasahara, Toshiro Yoshimura, Masakatsu Motomura, Nobuaki Yoshida, David Beeson, Shin’ichi Takeda, Yuji Yamanashi
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Journal Title
Science
Volume: 345
Issue: 6203
Pages: 1505-1508
DOI
Related Report
Peer Reviewed / Open Access
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