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Pathogenic role of mitochondrial DNA in neuromyelitis optica spectrum disorder

Research Project

Project/Area Number 18K15451
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 52020:Neurology-related
Research InstitutionOsaka University

Principal Investigator

Yamashita Kazuya  大阪大学, 医学系研究科, 招へい教員 (40774518)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsミトコンドリアDNA / NMOSD / 自然免疫 / インフラマソーム / NMO
Outline of Final Research Achievements

We investigated the role of mitochondrial DNA (mtDNA) in NMO spectrum disorder (NMOSD) pathology. Extracellular mtDNA is specifically elevated in the cerebrospinal fluid of patients with acute phase NMOSD, and mtDNA released by AQP4-Ab-mediated cellular damage elicits the innate immune cascades via TLR9 and NLRP3 inflammasomes pathways. Inflammasomes contribute to microglial activation and lesion formation in the focal NMOSD mice model.
Our study highlights mtDNA-mediated innate immune pathways as a novel therapeutic target for future treatment of NMOSD patients.

Academic Significance and Societal Importance of the Research Achievements

NMOSDにおいて抗AQP4の病原性はすでに証明され、ステロイドパルス療法や血漿交換が急性期治療として確立されている。しかし失明・四肢麻痺など重篤な後遺症が残存する症例が依然として多く存在しており、病態解明の追求および新規治療ターゲットの同定が急務であった。本研究でNMOSDの病態における自然免疫系を起点とした炎症促進機序を証明したことは、新たな治療法の開発に寄与する可能性がある。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (6 results)

All 2020 2019 2018

All Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (4 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Mitochondrial DNA enhance innate immune responses in neuromyelitis optica by monocyte recruitment and activation2020

    • Author(s)
      Mikito Shimizu, Tatsusada Okuno, Makoto Kinoshita, Hisae Sumi, Harutoshi Fujimura, Kazuya Yamashita, Tomoyuki Sugimoto, Shuhei Sakakibara, Kaori Sakakibara, Toru Koda, Satoru Tada, Teruyuki Ishikura, Hisashi Murata, Shohei Beppu, Naoyuki Shiraishi, Yasuko Sugiyama, Yuji Nakatsuji, Atsushi Kumanogoh & Hideki Mochizuki
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 13274-13274

    • DOI

      10.1038/s41598-020-70203-x

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cerebrospinal fluid mitochondrial DNA in neuromyelitis optica spectrum disorder2018

    • Author(s)
      Yamashita Kazuya、Kinoshita Makoto、Miyamoto Katsuichi、Namba Akiko、Shimizu Mikito、Koda Toru、Sugimoto Tomoyuki、Mori Yuki、Yoshioka Yoshichika、Nakatsuji Yuji、Kumanogoh Atsushi、Kusunoki Susumu、Mochizuki Hideki、Okuno Tatsusada
    • Journal Title

      Journal of Neuroinflammation

      Volume: 15 Issue: 1 Pages: 125-125

    • DOI

      10.1186/s12974-018-1162-0

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Pathogenic role of mitochondrial DNA through NLRP3 inflammasome in vitro and in vivo mouse model of neuromyelitis optica spectrum disorder2019

    • Author(s)
      Kazuya Yamashita
    • Organizer
      ECTRIMS 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cerebrospinal fluid mitochondrial DNA elicits innate immune response in NMO spectrum disorder2018

    • Author(s)
      山下和哉, 木下允, 宮本勝一, 南波明子, 清水幹人, 甲田亨, 杉本知之, 中辻裕司, 熊ノ郷淳, 楠進, 奥野龍禎, 望月秀樹
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Research-status Report
  • [Presentation] NMOSDにおける髄液ミトコンドリアDNAの自然免疫 活性化機序に関する研究2018

    • Author(s)
      山下和哉、木下 允、宮本 勝一、南波 明子、清水 幹人、甲田 亨、杉本 知之、中辻 裕司、熊ノ郷 淳、楠 進、望月 秀樹、奥野 龍禎
    • Organizer
      第30回日本神経免疫学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Cerebrospinal fluid mitochondrial DNA elicits innate immune response in NMOSD2018

    • Author(s)
      Yamashita K, Kinoshita M, Miyamoto K, Namba A, Shimizu M, Koda T, Nakatsuji Y, Kumanogoh A, Kusunoki S, Mochizuki H, Okuno T
    • Organizer
      ECTRIMS
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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