Elucidation of pathogenic mechanisms of myasthenia gravis caused by MuSK antibodies using a new synchronized experimental animal model

• Project/Area Number: 21591102
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
• Principal Investigator: SHIGEMOTO Kazuhiro 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究部長 (40284400)
• Co-Investigator(Renkei-kenkyūsha): KONISHI Tetsuro 独立行政法人国立病院機構宇多野病院, 神経内科, 院長 (50426508)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥130,000 (Direct Cost: ¥100,000、Indirect Cost: ¥30,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2009: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 重症筋無力症 / 神経筋接合部 / MuSK / 動物疾患モデル / 治療薬 / 疾患モデル / muscle-specific kians / 重病筋無力症

Research Abstract

We generated a new animal model in which 100% of mice synchronously develop experimental animal model of myasthenia gravis after immunization with MuSK protein. Our model provides a valuable platform from which to evaluate the role of MuSK signaling in NMJ maintenance and the immune mechanisms and pathophysiology of MuSK-MG, and we propose that 3, 4-DAP may be effective as a symptomatic therapy.

Research Products

• [Journal Article] 3,4-Diaminopyridine improves neuromuscular transmission in a MuSK antibody-induced mouse model of myasthenia gravis (2012)
  • Author(s): Mori, S. , Kishi, M., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T., Konishi, T., Maruyama, N., and Shigemoto, K.
  • Journal Title: Journal of neuroimmunology Volume: 245 Issue: 1-2 Pages: 75-78
  • DOI: 10.1016/j.jneuroim.2012.02.010
  • Peer Reviewed
• [Journal Article] Antibodies against muscle-specific kinase impair both presynaptic and postsynaptic functions in a murine model of myasthenia gravis (2012)
  • Author(s): Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Hotta H, Desaki J, Kishi M, Konishi T, Nishino Y, Miyazawa A, Maruyama N, Shigemoto K
  • Journal Title: The American Journal of Pathology Volume: 180 Issue: 2 Pages: 617-28
  • DOI: 10.1016/j.ajpath.2011.10.031
  • Peer Reviewed
• [Journal Article] Divalent and monovalent autoantibodies cause dysfunction of MuSK by distinct mechanisms in a rabbit model of myasthenia gravis (2012)
  • Author(s): Mori, S. , Yamada, S., Kubo, S. , Chen, J., Matsuda, S. , Shudou, M. , Maruyama, N., and Shigemoto, K.
  • Journal Title: Journal of neuroimmunology Volume: 244 Issue: 1-2 Pages: 1-7
  • DOI: 10.1016/j.jneuroim.2011.12.005
  • Peer Reviewed
• [Journal Article] Galectin-7 as a marker of cholesteatoma residue and its detection during surgery by an immunofluorescent methodva preliminary study (2012)
  • Author(s): 高木大樹
  • Journal Title: Ontology and Neurotology Volume: 33 Issue: 3 Pages: 396
  • DOI: 10.1097/mao.0b013e3182488021
  • Peer Reviewed
• [Journal Article] サルコペニアの発症機構 (2011)
  • Author(s): 重本和宏,森秀一,宮崎剛,久保幸穂
  • Journal Title: 神経内科 Volume: 75(6) Pages: 584-588
• [Journal Article] シナプスを介したサルコペニアの発症メカニズムとバイオマーカー (2011)
  • Author(s): 重本和宏,森秀一、宮崎剛、久保幸穂
  • Journal Title: 日本老年医学会雑誌 Volume: 48(1) Pages: 42-43
  • NAID: 10030468993
• [Journal Article] 運動神経細胞とサルコペニア (2011)
  • Author(s): 重本和宏、森秀一、宮崎剛、久保幸穂
  • Journal Title: Modern Physician Volume: 131 Pages: 1308-11
• [Journal Article] Establishment and characterization of hepatocytes from an Immortomouse/SMP30/GNL knockout mouse hybrid lacking vitamin C to study vitamin C transport (2011)
  • Author(s): Amano, A., Handa, S., Aigaki, T., Shigemoto, K., Maruyama, N., Ishigami, A.
  • Journal Title: Journal of biochemistry Volume: 150 Issue: 6 Pages: 671-678
  • DOI: 10.1093/jb/mvr109
  • Peer Reviewed
• [Journal Article] シナプスを介したサルコペニアの発症メカニズムとバイオマーカー (2011)
  • Author(s): 重本和宏, 森秀一、宮崎剛、久保幸穂
  • Journal Title: 日本老年医学会雑誌 Volume: 48 Pages: 42-3
  • NAID: 10030468993
• [Journal Article] サルコペニアの発症機構 (2011)
  • Author(s): 重本和宏, 森秀一、宮崎剛、久保幸穂
  • Journal Title: 日本老年医学会雑誌 Volume: 75 Pages: 584-8
• [Journal Article] Muscle weakness and neuromuscular junctions in aging and disease (2010)
  • Author(s): Shigemoto, K., Kubo, S., Mori, S., Yamada, S., Akiyoshi, T., and Miyazaki, T.
  • Journal Title: Geriatr Gerontol Int 10 Suppl Volume: 1 Issue: s1 Pages: 137-147
  • DOI: 10.1111/j.1447-0594.2010.00608.x
  • NAID: 10027273521
  • Peer Reviewed
• [Journal Article] 抗MuSK抗体 (2010)
  • Author(s): 大田潔江、大田光煕,重本和宏
  • Journal Title: 日本臨床 Volume: 68 Pages: 633-6
• [Journal Article] 神経筋接合部の異常と筋萎縮 (2010)
  • Author(s): 重本和宏,森秀一,久保幸穂,山田茂,秋好沢諭,宮崎剛
  • Journal Title: メジカルビュー社.老年医学 Pages: 135-144
• [Journal Article] Muscle weakness and neuromuscular junction in aging and disease. (2010)
  • Author(s): Shigemoto, K., Kubo, S., Mori, S., Yamada, S., Akiyoshi, T., Miyazaki, T.
  • Journal Title: Geriatr.Gerintol.Int. Volume: 10
  • NAID: 10027273521
  • Peer Reviewed
• [Journal Article] 神経筋接合部位の異常と筋力低下 (2009)
  • Author(s): 重本和宏、久保幸穂、丸山直記
  • Journal Title: 日本老年医学会雑誌 Volume: 46(2) Pages: 106-113
  • NAID: 10024963928
• [Journal Article] サルコペニア(加齢性筋肉減少症)とそのバイオマーカー (2009)
  • Author(s): 重本和宏、丸山直記
  • Journal Title: 老年医学 Volume: 47(6) Pages: 733-735
• [Journal Article] The role of zinc finger protein 521/early hematopoietic zincfinger protein in erythroid cell differentiation (2009)
  • Author(s): Matsubara, E., Sakai, I., Yamanouchi, J., Fujiwara, H., Yakushijin, Y., Hato, T., Shigemoto, K., Yasukawa, M.
  • Journal Title: J Biol Chem 284 Pages: 3480-3487
  • Peer Reviewed
• [Journal Article] 神経筋接合部位の異常と筋力低下 (2009)
  • Author(s): 重本和宏、久保幸穂、丸山直記
  • Journal Title: 日本老年医学会雑誌 46 Pages: 106-113
  • NAID: 10024963928
• [Journal Article] サルコペニア(加齢性筋肉減少症)とそのバイオマーカー (2009)
  • Author(s): 重本和宏、丸山直記
  • Journal Title: 老年医学 47 Pages: 733-735
• [Presentation] 抗MuSK抗体陽性重症筋無力症の発症メカニズムに基づく治療薬の検討 (2012)
  • Author(s): 森秀一,久保幸穂,岸雅彦,小西哲郎,重本和宏
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2012-05-25
• [Presentation] A new synchronized model of myasthenia gravis caused by anti-MuSK antibodies (2012)
  • Author(s): Shigemoto, K
  • Organizer: International Conference on Nervous System Autoimmunity
  • Place of Presentation: Bangalore, India
• [Presentation] Distinct mechanisms between divalent and monovalent MuSK antibodies involved with dysfunction of MuSK leading to myasthenia gravis (2011)
  • Author(s): Mori S, Kubo S, Yamada S, Miyazaki T, Shigemoto K
  • Organizer: Society for Neuroscience
  • Place of Presentation: Washington DC
  • Year and Date: 2011-11-15
• [Presentation] サルコペニアのメカニズム解明に向けて (2011)
  • Author(s): 重本和宏
  • Organizer: 第33回日本基礎老化学会シンポジウム
  • Place of Presentation: 名古屋大学
  • Year and Date: 2011-10-08
• [Presentation] MuSKとDok-7の相互作用は神経筋シナプスの維持に重要である (2011)
  • Author(s): 森秀一,重本和宏
  • Organizer: 第66回日本体力医学会大会
  • Place of Presentation: 下関
  • Year and Date: 2011-09-17
• [Presentation] Distinct mechanisms between divalent and monovalent MuSK antibodies involved with dysfunction of MuSK leading to myasthenia gravis (2011)
  • Author(s): Mori S, Kubo S, Yamada S, Miyazaki T, Shigemoto K
  • Organizer: 第34回日本神経科学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2011-09-15
• [Presentation] Distinct mechanisms between divalent and monovalent MuSK antibodies involved with dysfunction of MuSK leading to myasthenia gravis (2011)
  • Author(s): Mori S, Kubo S, Yamada S, Miyazaki T, Shigemoto K
  • Organizer: Society for Neuroscience
  • Place of Presentation: Washington, D. C
• [Presentation] サルコペニアのメカニズム解明に向けて (2011)
  • Author(s): 重本和宏
  • Organizer: 第33回日本基礎老化学会シンポジウム
  • Place of Presentation: 野田
• [Presentation] Strategy to treatment of myasthenia gravis caused by MuSK antibodies using a synchronized experimental animal model (2010)
  • Author(s): Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Shigemoto K
  • Organizer: Society for Neuroscience
  • Place of Presentation: San Diego
  • Year and Date: 2010-11-17
• [Presentation] New strategy to treatment of myasthenia gravis caused by MuSK antibodies using a synchronized experimental animal model (2010)
  • Author(s): Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Shigemoto K
  • Organizer: 第33回日本神経科学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-09-03
• [Presentation] 筋は逆行性シグナルにより筋・運動神経を維持する (2010)
  • Author(s): 森秀一,久保幸穂,秋好沢諭,山田茂,宮崎剛,重本和宏
  • Organizer: 第33回日本基礎老化学会大会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-06-18
• [Presentation] Complement activation is dispensable for myasthenia gravis caused by MuSK antibodies (2010)
  • Author(s): Shigemoto K, Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T
  • Organizer: 10th International Congress of Neuroimmunology
  • Place of Presentation: Barcelona, Spain
• [Presentation] New strategy to treatment of myasthenia gravis caused by MUSK antibodies using a synchronized experimental animal model (2010)
  • Author(s): Mori, S., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T., Shigemoto, K.
  • Organizer: 第33回日本神経科学会大会
  • Place of Presentation: 神戸
• [Presentation] Complement activation is dispensable for myasthenia gravis caused by MUSK antibodies. (2010)
  • Author(s): Shigemoto, K, Mori, S., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T
  • Organizer: 10th International Congress of Neuroimmunology
  • Place of Presentation: Barcelona
• [Presentation] Strategy to treatment of myasthenia gravis caused by MUSK antibodies using a synchronized experimental animal model. (2010)
  • Author(s): Mori, S., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T., Shieemoto, K
  • Organizer: Society for Neuroscience 2010
  • Place of Presentation: San Diego
• [Presentation] Activation of complement is indispensable for myasthenia gravis caused by MuSK antibodies (2009)
  • Author(s): Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Shigemoto K
  • Organizer: Society for Neuroscience
  • Place of Presentation: Chicago
  • Year and Date: 2009-10-17
• [Presentation] Activation of complement is indispensable for myasthenia gravis caused by MuSK antibodies (2009)
  • Author(s): 森秀一, 久保幸穂, 秋好沢諭, 山田茂, 宮崎剛, 重本和宏
  • Organizer: Society for Neuroscience 2009
  • Place of Presentation: Chicago
  • Year and Date: 2009-10-17
• [Presentation] Activation of complement is indispensable for myasthenia gravis caused by MuSK antibodies (2009)
  • Author(s): Mori S, Kubo S, Akiyoshi T, Yamada S, Shigemoto K
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-09-19
• [Presentation] MuSKは神経筋シナプスの維持に重要である.研究モデル動物の確立 (2009)
  • Author(s): 森秀一,久保幸穂,秋好沢諭,山田茂,宮崎剛,重本和宏
  • Organizer: 第32回日本基礎老化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2009-06-27
• [Presentation] MuSKは神経筋シナプスの維持に重要である ～研究モデル動物の確立～ (2009)
  • Author(s): 森秀一, 久保幸穂, 秋好沢諭, 山田茂, 宮崎剛, 重本和宏
  • Organizer: 第32回日本基礎老化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2009-06-27
• [Book] 運動神経細胞とサルコペニア (2011)
  • Author(s): 重本和宏, 森秀一、宮崎剛、久保幸穂
  • Total Pages: 2
  • Publisher: 新興医学出版社
• [Book] 老年医学update 2010-2011 (2010)
  • Author(s): 重杢租家、森秀一、久保幸穂、山田茂、秋好沢諭、宮崎剛
  • Total Pages: 184
  • Publisher: メディカルビュー社
• [Book] The Immunopathogenesis of Experimental Autoimmune Myasthenia Gravis Induced by Autoantibodies against Muscle-specific kinase. Book title : Myasthenia gravis Diseas Mechanisms and Immune Intervention. Editor : Premkumar Christadoss (2009)
  • Author(s): Shigemoto, K. Kubo, S. Mori. S. Yamada, S. Miyazaki, T. Akiyoshi, T and Maruyama, S
  • Publisher: Linus Publication, Inc.
• [Book] Myasthenia gravis Disease Mechanisms and Immune Intervention (2009)
  • Author(s): Shigemoto, K., Kubo, S., Mori.S., Yamada, S., Miyazaki, T., Akiyoshi, T, Maruyama, S.
  • Total Pages: 20
  • Publisher: Linus Publication, Inc.
• [Remarks] The Jackson Laboratory, USA
  • URL: http://jaxmice.jax.org/news/2012/Myasthenia_gravis.html
• [Remarks] The Jackson Laboratory, USA Podcast
  • URL: http://jaxmice.jax.org/multimedia/podcasts/20120524-Shigemoto.mp3
• [Remarks] 東京都健康長寿医療センター研究所老年病研究チーム運動器医学
  • URL: http://www.tmghig.jp/J_TMIG/j_research/DA33.html
• [Remarks]
  • URL: http://www.tmghig.jp/J_TMIG/j_research/DA33.html