• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Molecular approaches to identify the novel therapeutic targets for the encephalitis associated with neuronal surface antibodies

Research Project

Project/Area Number 20K07875
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52020:Neurology-related
Research InstitutionNihon University

Principal Investigator

HARA Makoto  日本大学, 医学部, 准教授 (10817224)

Co-Investigator(Kenkyū-buntansha) 中嶋 秀人  日本大学, 医学部, 教授 (20330095)
大日方 大亮  日本大学, 医学部, 准教授 (20624886)
藤原 恭子  日本大学, 歯学部, 准教授 (40595708)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords神経細胞表面抗体 / RNAシークエンス / パスウェイ解析 / 培養海馬神経細胞 / 抗体作用 / 初代培養神経細胞 / qPT PCR / 免疫染色 / 抗体精製 / 自己免疫性脳炎 / マイクロアレイ / 創薬
Outline of Research at the Start

自己免疫性脳炎は治療の遅れが重症化につながる疾患群であり、発症や進行には神経細胞膜表面の蛋白を標的とする自己抗体が重要な役割を担っています。しかし、それぞれの抗体が引き起こす神経細胞障害のメカニズムは不明です。私たちはラット脳を用いて脳炎患者の血清・脳脊髄液から自己抗体群を迅速に抽出/精製する手法を確立し、それらの抗体群が細胞表面標的蛋白の発現を低下させることを見いだしました。本研究では、自己免疫性脳炎患者から抽出した精製抗体と培養神経細胞を用いて、抗体が標的とする細胞応答経路を同定するために発現遺伝子を網羅的に解析し、標的遺伝子を制御する化合物を作製して日本発の革新的創薬を目指します。

Outline of Final Research Achievements

A total of 48 patients, who were previously considered to have diseases of unknown etiology, were newly identified with encephalitis associated with antineuronal surface antibodies (NSAs) using in-house screening and confirmation assays for NSAs. NSA types detected were as follows: NMDAR in 26, LGI1 in 9, GABABR in 8, CASPR2 in 3, and AMPAR in 2 patients. An investigation of antibody effects using primary live neurons from rodents revealed that anti-NMDAR IgG affected the G protein-coupled receptor signaling pathway in the antibody-treated neurons that decreased the levels of messenger RNA and density of the neuronal surface mGluR8 clusters.

Academic Significance and Societal Importance of the Research Achievements

抗神経細胞表面抗体群が神経細胞表面の抗原に結合することで引き起こされる細胞内経路への影響については一切検討されていなかった。本研究により、自己免疫性脳炎で最も頻度の多い抗NMDA受容体脳炎において、NMDA受容体抗体が細胞内シグナル伝達経路へもたらす影響及び、そのパスウェイで中心的役割を担う膜受容体の発現低下が確認された。抗体により影響される細胞内シグナル経路が特定されたことで、今後、細胞内シグナル経路を標的にした病態に選択性の高い創薬へとつながる可能性がある。

Report

(3 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (5 results)

All 2022 2021 2020

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (3 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Novel qEEG Biomarker to Distinguish Anti-NMDAR Encephalitis From Other Types of Autoimmune Encephalitis.2022

    • Author(s)
      Mizoguchi Tomotaka, Hara Makoto, Hirose Satoshi, Nakajima Hideto
    • Journal Title

      Frontiers in Immunology

      Volume: 13

    • DOI

      10.3389/fimmu.2022.845272

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Practical approach for the diagnosis of disorders associated with antibodies against neuronal surface proteins2020

    • Author(s)
      Hara Makoto、Nakajima Hideto、Kamei Satoshi
    • Journal Title

      Neurology and Clinical Neuroscience

      Volume: 9 Issue: 1 Pages: 56-62

    • DOI

      10.1111/ncn3.12462

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] AUTOANTIBODY SCREENING USING ASSAYS WITH RAT BRAIN TISSUE AND CULTURED NEURONS FACILITATES PROMPT INDUCTION OF IMMUNOTHERAPY FOR AUTOIMMUNE ENCEPHALITIS2021

    • Author(s)
      Makoto Hara、Yuki Yokota、Satoko Ninomiya、Satoshi Kamei、Hideto Nakajima
    • Organizer
      第17回アジア・オセアニア神経学会議
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Autoantibody screening using an in-house tissue-based assay facilitates prompt induction of immunotherapy for autoimmune encephalitis2021

    • Author(s)
      Makoto Hara、Yuki Yokota、Satoko Ninomiya、Satoshi Kamei、Hideto Nakajima
    • Organizer
      American Academy of Neurology Annual Meeting 2021
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Analyses of immunolabeling patterns using a tissue-based assay can predict anti-NMDAR encephalitis2020

    • Author(s)
      Hara Makoto
    • Organizer
      第61回日本神経学会学術大会
    • Related Report
      2020 Research-status Report

URL: 

Published: 2020-04-28   Modified: 2024-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi