The relationship between inflammasomes and the endoplasmic reticulum stress response in the injured spinal cord

• Project/Area Number: 16K10839
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Tokai University
• Principal Investigator: WATANABE Masahiko 東海大学, 医学部, 教授 (40220925)
• Co-Investigator(Kenkyū-buntansha): 隅山 香織 東海大学, 医学部, 准教授 (20433914) ; 加藤 裕幸 東海大学, 医学部, 講師 (40348678)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 脊髄損傷 / オリゴデンドロサイト / オリゴデンドロサイト前駆細胞 / 小胞体ストレス応答 / インフラマソーム / GLP-1受容体作動薬 / 小胞体ストレス / マクロファージ / GLP-1受動体作動薬 / アポトーシス

Outline of Final Research Achievements

Apoptosis is a key factor in the secondary injury process after spinal cord injury that aggravates the damage to the injured spinal cord, and endoplasmic reticulum stress is one of the main apoptosis pathways in the central nervous system. Apoptosis hinders the survival and differentiation of oligodendrocyte progenitor cells (OPCs) that proliferate after spinal cord injury, impeding remyelination and functional recovery. We investigated the role of inflammasomes in the injured spinal cord, which is involved in the ER stress pathway, and showed significantly higher expression of inflammasomes after spinal cord injury, especially in OPCs. We also investigated the effect of a GLP-1 receptor agonist, which also enhances the ER stress response. GLP-1 receptor agonist administration enhanced OPC survival and differentiation and brought about improved motor function, showing great potential for the treatment of SCI.

Academic Significance and Societal Importance of the Research Achievements

外傷性脊髄損傷における障害は二次障害により拡大するが、その主体をなすのがアポトーシスであり、中枢神経では小胞体ストレスが重要な経路である．アポトーシスは損傷の拡大に加えて、再生のために誘導・増殖されたオリゴデンドロサイト前駆細胞（OPC）の生存分化も障害し、再髄鞘形成を阻害する．すなわち損傷脊髄内でのグリア細胞のアポトーシス抑制が可能であれば、二次障害による損傷範囲拡大の軽減、再髄鞘形成による脊髄損傷後の麻痺の軽減へとつながる可能性がある．われわれは二次障害の主因である小胞体ストレス応答に着目し研究し良好な結果を得ており、今後の臨床応用を目指している．

Research Products

• [Journal Article] The relationship between inflammasomes and the endoplasmic reticulum stress response in the injured spinal cord (2019)
  • Author(s): Sho Yanagisawa, Masahiko Watanabe, Hiroyuki Katoh, Takeshi Imai, Satoshi Nomura, Toshihiro Noguchi
  • Journal Title: Neuroscience Letters Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Amiloride Promotes Oligodendrocyte Survival and Remyelination after Spinal Cord Injury in Rats (2018)
  • Author(s): Takeshi Imai, Hiroyuki Katoh, Kaori Suyama, Masahiro Kuroiwa, Sho Yanagisawa and Masahiko Watanabe.
  • Journal Title: J. Clin. Med. Volume: 7 Issue: 3 Pages: 1-13
  • DOI: 10.3390/jcm7030046
  • Peer Reviewed / Open Access
• [Presentation] 脊髄損傷におけるGLP‐１受容体作動薬の作用 - 小胞体ストレス応答の増強 (2018)
  • Author(s): 野村慧、加藤裕幸、今井洸、野口俊洋、渡辺雅彦
  • Organizer: 第33回日本整形外科学会基礎学術集会
• [Presentation] The effect of the GLP-1 receptor agonist on spinal cord injury - by enhancing the ER stress response (2018)
  • Author(s): Satoshi Nomura, Hiroyuki Katoh, Toshihiro Noguchi, Masahiko Watanabe
  • Organizer: Orthopaedic Research Society 2019
  • Int'l Joint Research
• [Presentation] Administration of the GLP-1 receptor agonist exenatide enhances the ER stress response and improves functional recovery after spinal cord injury (2018)
  • Author(s): Masahiko Watanabe, Satoshi Nomura, Hiroyuki Katoh
  • Organizer: 57th International Spinal Cord Society
  • Int'l Joint Research
• [Presentation] The effect of the GLP-1 receptor agonist on spinal cord injury - by enhancing the ER stress response (2018)
  • Author(s): Nomura S, Katoh H, Yanagiswa S, Imai T, Kuroiwa M, Watanabe M
  • Organizer: Orthopaedic Research Society 2018
• [Presentation] Activation of NLRP3 inflammasomes in a rat spinal cord injury model. (2017)
  • Author(s): Sho Yanagisawa, Hiroyuki Katoh, Takeshi Imai, Masahiro Kuroiwa, Masahiko Watanabe
  • Organizer: Orthopaedic Research Society 2017
  • Place of Presentation: San Diego Convention Center (San Diego)
  • Year and Date: 2017-03-18
• [Presentation] 脊髄損傷におけるGLP‐１受容体作動薬の効果と小胞体ストレス応答による作用の解明 (2017)
  • Author(s): 野村慧、加藤裕幸、柳澤聖、今井洸、黒岩真弘、渡辺雅彦
  • Organizer: 第32回日本整形外科学会基礎学術集会
• [Presentation] The effect of the GLP-1 receptor agonist on spinal cord injury - by enhancing the ER stress response (2017)
  • Author(s): Nomura S, Katoh H, Yanagiswa S, Imai T, Kuroiwa M, Watanabe M
  • Organizer: Neurosience 2017
  • Int'l Joint Research
• [Presentation] 脊髄損傷に対するGLP‐１受容体作動薬の治療効果 (2017)
  • Author(s): 加藤裕幸、野村慧、柳澤聖、今井洸、黒岩真弘、渡辺雅彦
  • Organizer: 第53回日本脊髄障害医学会
• [Presentation] Activation of NLRP3 inflammasomes in a rat spinal cord injury model. (2016)
  • Author(s): Sho Yanagisawa, Hiroyuki Katoh, Takeshi Imai, Masahiro Kuroiwa, Masahiko Watanabe
  • Organizer: Neurosciense2016
  • Place of Presentation: San Diego Convention Center (San Diego)
  • Year and Date: 2016-11-13
• [Presentation] 損傷脊髄におけるインフラマソーム構成タンパクの発現－細胞種による違い－ (2016)
  • Author(s): 柳澤 聖、加藤裕幸、今井洸、黒岩真弘、渡辺雅彦
  • Organizer: 第32回日本整形外科学会基礎学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-10-13
• [Presentation] 損傷脊髄におけるインフラマソーム構成タンパクの発現 (2016)
  • Author(s): 柳澤 聖、加藤裕幸、今井洸、黒岩真弘、松山大輔、渡辺雅彦
  • Organizer: 第35回日本運動器移植再生医学研究会
  • Place of Presentation: 広島県医師会館（広島県広島市）