Screening of a novel drug to activate the formation of neuromuscular junctions

• Project/Area Number: 24659673
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Nagoya University
• Principal Investigator: HIRATA Hitoshi 名古屋大学, 医学(系)研究科(研究院), 教授 (80173243)
• Co-Investigator(Kenkyū-buntansha): KURIMOTO Shigeru 名古屋大学, 医学系研究科, 特任講師 (70597856) ; OHNO Kinji 名古屋大学, 医学系研究科, 教授 (80397455) ; TORIHASHI Shigeko 名古屋大学, 医学系研究科, 教授 (90112961) ; MIZUSHIMA Hideyuki 名古屋大学, 医学部附属病院, 病院助教 (80718403) ; 夏目 唯弘 名古屋大学, 医学部附属病院, その他 (30624316)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 再生医療 / 神経筋接合部 / drug repositioning / 神経再支配

Outline of Final Research Achievements

During the formation of neuromuscular junctions (NMJs), binding of agrin to LRP4 induces MuSK phosphorylation, which activates ATF2 downstream of JNK and induces clustering of acetylcholine receptors (AChRs). We used the drug repositioning strategy, in which a drug already used for a specific disease is applied to treat another disease, to identify an FDA-approved drug that enhances the agrin/LRP4/MuSK signaling and NMJ formation. Drug A increases MuSK phosphorylation in dose-dependent manner. In C2C12 myotubes, number of AChR clusters were increased in the presence of Drug A together with agrin.
Moreover, drug A increases the expression of AChR-e, rapsyn and Col-Q mRNAs in neurotization model mice.

Research Products

• [Journal Article] Transplantation of embryonic motor neurons into peripheral nerve combined with functional electrical stimulation restores functional muscle activity in the rat sciatic nerve transection model. (2013)
  • Author(s): Kurimoto S, Kato S, Nakano T, Yamamoto M, Takanobu N, Hirata H.
  • Journal Title: J Tissue Eng Regen Med Volume: -
  • NAID: 120005981188
• [Presentation] 神経筋接合部形成促進薬の探索 (2015)
  • Author(s): 石井久雄、栗本秀、平田仁
  • Organizer: 第58回日本手外科学会学術集会
  • Place of Presentation: 東京都新宿区 京王プラザホテル
  • Year and Date: 2015-04-16 – 2015-04-17
• [Presentation] 神経筋接合部形成促進薬の探索 (2014)
  • Author(s): 石井久雄、栗本秀、平田仁
  • Organizer: 第29回日本整形外科学会基礎学術集会
  • Place of Presentation: 鹿児島県鹿児島市 城山観光ホテル
  • Year and Date: 2014-10-09 – 2014-10-10
• [Presentation] Transplanted cell number is a key factor for success of ambulation function restoration by Motoneuron Integrated Striated Muscles (MISM) (2014)
  • Author(s): Kato S, Kurimoto S, Nakano T, Ishii H, Arai T, Natsume T, Iwatsuki K, Ota H, Onishi T, Nishizuka T, Kurahashi T, Hirata H
  • Organizer: Orthopaedic Research Society
  • Place of Presentation: New Orleans, USA
• [Presentation] ＭＩＳＭ技術を用いた機能再建 (2013)
  • Author(s): 平田仁 下田真吾
  • Organizer: 日本整形外科学会
  • Place of Presentation: リーガロイヤルホテル（広島市）
• [Presentation] Motoneuron Integrated Striated Muscles (MISM)による麻痺再建における (2013)
  • Author(s): 加藤宗一 中野智則 石井久雄 平田仁
  • Organizer: 日本末梢神経学会
  • Place of Presentation: 朱鷺メッセ（新潟市）
• [Presentation] Transplanted cell number is important for success of ambulation function restoration by Motoneuron Integrated Striated Muscles (MISM) (2013)
  • Author(s): 加藤宗一 中野智則 石井久雄 平田仁
  • Organizer: Annual Meeting of the American Society for Surgery of the Hand
  • Place of Presentation: Sanfrancisco, USA