Therapeutic strategy for muscular dystrophy via regulation of STIM1 mediated Ca2+ homeostasis

• Project/Area Number: 15K09328
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Teikyo University
• Principal Investigator: Shimizu Teruo 帝京大学, 医療技術学部, 特任教授 (00107666)
• Co-Investigator(Kenkyū-buntansha): 真先 敏弘 帝京科学大学, 医療科学部, 教授 (00585028) ; 萩原 宏毅 帝京科学大学, 医療科学部, 教授 (80276732)
• Co-Investigator(Renkei-kenkyūsha): Matsumura Kiichiro 帝京大学, 医学部, 教授 (50260922) ; Saito Fumiaki 帝京大学, 医学部, 准教授 (40286993)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 筋ジストロフィー / 細管集合体ミオパチー / カルシウムホメオスタシス / STIM1 / ORAI1

Outline of Final Research Achievements

Recently, STIM1-ORAI1 signaling is receiving attention as molecules regulating calcium homeostasis in skeletal muscle. In this study, we investigated the pathomechanism of a novel mutation of STIM1 we identified in a family with tubular aggregate myopathy. In contrast to the previous reports, this novel mutation resides in the cytoplasmic domain of STIM1. Gene transfer experiments using cultured myoblasts exhibit that the mutant STIM1 induces marked reduction of intracellular calcium concentration and inhibits puncta formation of STIM1 with tapsigargin, which is necessary for ORAI1 activation. Taken together, in the family with the novel mutation, tubular aggregate myopathy is caused by a distinct pathomechanism from that previously proposed, i.e. excessive influx of calcium.

Research Products

• [Journal Article] Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1 (2016)
  • Author(s): Oakum H, Saito F, Jun Mitsui J, Hara Y, Hatanaka Y, Ikeda M, Shimizu T, Matsumura K, Shimizu J, Tsui S, Sonoo M.
  • Journal Title: Neurol Genet Volume: 2:e50 Issue: 1 Pages: 50-50
  • DOI: 10.1212/nxg.0000000000000050
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Excision of myotonic dystrophy CTG repeat using CRISPR/Cas9 genome editting (2017)
  • Author(s): 斉藤史明、池田美樹、萩原宏毅、真先敏弘、清水輝夫、松村喜一郎、園生雅弘
  • Organizer: 第3回日本筋学会学術終会
• [Presentation] 筋強直性ジストロフィーに対するゲノム編集治療の基礎的研究 (2017)
  • Author(s): 斉藤史明、池田美樹、萩原宏毅、真先敏弘、清水輝夫、松村喜一郎、園生雅弘
  • Organizer: 第2回日本ゲノム編集学会
• [Presentation] Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1. (2016)
  • Author(s): Saito F, Okuma H, Mitsui J, Hara Y, Hatanaka Y, Ikada M, Shimizu T, Matsumura K, Shimizu J, Tsuji S, Sonoo M
  • Organizer: 21st International congress of the World Muscle Society
  • Place of Presentation: スペイン・グラナダ
  • Year and Date: 2016-10-04
  • Int'l Joint Research
• [Presentation] Novel mutation of STIM1 causes dysregulation of Ca2+ homeostasis in tubular aggregate myopathy. (2016)
  • Author(s): 斉藤史明、原雄二、三井純、畑中裕己、萩原宏毅、真先敏弘、清水輝夫、清水潤、辻省次、松村喜一郎、園生雅弘
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2016-05-18
• [Presentation] α-dystroglycan N末端ドメインの過剰発現がマウス骨格筋に及ぼす影響に関する検討 (2015)
  • Author(s): 斉藤史明、大熊秀彦、池田美樹、萩原宏毅、真先敏弘、清水輝夫、松村喜一郎、園生雅弘．
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会合同大会）
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Tubular aggregate myopathyにおける新規STIM1変異と筋芽細胞に及ぼす影響 (2015)
  • Author(s): 大熊秀彦、三井純、大森亜希、肥田あゆみ、畑中裕己、松村喜一郎、清水潤、 辻省次、園生雅弘、斉藤史明．
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟コンベンションセンター（新潟県新潟市）
  • Year and Date: 2015-05-20
• [Presentation] Analysis of the functional role of α-dystroglycan N-terminal domain in vivo (2015)
  • Author(s): 斉藤史明、大熊秀彦、萩原宏毅、真先敏弘、池田美樹、清水輝夫、園生雅 弘、松村喜一郎．
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟コンベンションセンター（新潟県新潟市）
  • Year and Date: 2015-05-20