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Discovery of new drug target modifiying the function of blood-brain barrier and blood-nerve barrier

Research Project

Project/Area Number 18K07526
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

Shimizu Fumitaka  山口大学, 医学部附属病院, 助教 (90535254)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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自己免疫性神経疾患 / 血液脳関門 / GRP78抗体 / 視神経脊髄炎 / 傍腫瘍性小脳変性症 / 血液神経関門 / 新規抗体製剤開発 / 細胞モデル / 神経免疫疾患 / 自己免疫性ニューロパチー
Outline of Final Research Achievements

Objective: The purpose of this project is to develop the assay for identifying the antigen against IgG from the patients with neuro-inflammatory disorders, which cause the BBB disruption using our human in vitro BBB model. Methods: We identified IgG from patients with the neuro-inflammatory disease, which induced NF-κB p65 nuclear translocation in human brain microendothelial cell lines (TY10). We developed the novel assay to detect cell-surface antigen against IgG from the neuro-inflammatory disease. Results: IgGs from paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome (LEMS) [LEMS-PCD] shows the most ability to give rise to nuclear translocation of NF-κB p65. We detected glucose-regulated protein (GRP)78 autoantibodies in the IgG of LEMS-PCD. Conclusions: We identified GRP78 autoantibodies from LEMS-PCD patients having biological effects on BBB-endothelial cells.

Academic Significance and Societal Importance of the Research Achievements

傍腫瘍性小脳変性症を合併したランバート・イートン筋無力症の発症機序が明らかとなった.GRP78は癌細胞とBBB構成内皮細胞の細胞表面に多く発現しており,細胞表面に発現するGRP78はNF-κBシグナル活性に関与する.さらに,担癌患者では血中にGRP78抗体が検出されることが報告されている.傍腫瘍性小脳変性症を合併したランバート・イートン筋無力症発症の病態機序として,GRP78とP/Q型VGCCは癌細胞表面に発現しており,腫瘍との交差免疫により産生されたGRP78抗体によるBBB破綻が,同じ機序より産生されたP/Q型VGCC抗体の脳内流入を促進し小脳機能障害を惹起する可能性が考えられた.

Report

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

    (27 results)

All 2020 2019 2018

All Journal Article (13 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 9 results,  Open Access: 4 results) Presentation (14 results) (of which Int'l Joint Research: 3 results,  Invited: 2 results)

  • [Journal Article] 総説 ペリサイトと神経系-生理的役割と病理的意義2020

    • Author(s)
      清水 文崇、神田 隆
    • Journal Title

      BRAIN and NERVE

      Volume: 72 Issue: 2 Pages: 151-158

    • DOI

      10.11477/mf.1416201495

    • ISSN
      1344-8129, 1881-6096
    • Year and Date
      2020-02-01
    • Related Report
      2020 Annual Research Report
  • [Journal Article] Advancing human induced pluripotent stem cell‐derived blood‐brain barrier models for studying immune cell interactions2020

    • Author(s)
      Nishihara Hideaki、Gastfriend Benjamin D.、Soldati Sasha、Perriot Sylvain、Mathias Amandine、Sano Yasuteru、Shimizu Fumitaka、Gosselet Fabien、Kanda Takashi、Palecek Sean P.、Du Pasquier Renaud、Shusta Eric V.、Engelhardt Britta
    • Journal Title

      The FASEB Journal

      Volume: 34 Issue: 12 Pages: 16693-16715

    • DOI

      10.1096/fj.202001507rr

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Serotonin/5-HT1A Signaling in the Neurovascular Unit Regulates Endothelial CLDN5 Expression2020

    • Author(s)
      Sugimoto Kotaro、Ichikawa-Tomikawa Naoki、Nishiura Keisuke、Kunii Yasuto、Sano Yasuteru、Shimizu Fumitaka、Kakita Akiyoshi、Kanda Takashi、Imura Tetsuya、Chiba Hideki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 1 Pages: 254-254

    • DOI

      10.3390/ijms22010254

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Contribution of brain pericytes in blood-brain barrier formation and maintenance: a transcriptomic study of cocultured human endothelial cells derived from hematopoietic stem cells2020

    • Author(s)
      Heymans Marjolein、Figueiredo Ricardo、Dehouck Lucie、Francisco David、Sano Yasuteru、Shimizu Fumitaka、Kanda Takashi、Bruggmann Rumy、Engelhardt Britta、Winter Peter、Gosselet Fabien、Culot Maxime
    • Journal Title

      Fluids and Barriers of the CNS

      Volume: 17 Issue: 1 Pages: 37-37

    • DOI

      10.1186/s12987-020-00208-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Design and Validation of a Human Brain Endothelial Microvessel-on-a-Chip Open Microfluidic Model Enabling Advanced Optical Imaging2020

    • Author(s)
      Salman Mootaz M.、Marsh Graham、Kusters Ilja、Delinc Matthieu、Di Caprio Giuseppe、Upadhyayula Srigokul、de Nola Giovanni、Hunt Ronan、Ohashi Kazuka G.、Gray Taylor、Shimizu Fumitaka、Sano Yasuteru、Kanda Takashi、Obermeier Birgit、Kirchhausen Tom
    • Journal Title

      Frontiers in Bioengineering and Biotechnology

      Volume: 8 Pages: 573755-573755

    • DOI

      10.3389/fbioe.2020.573775

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of a human in vitro blood-brain tumor barrier model of diffuse intrinsic pontine glioma to better understand the chemoresistance2020

    • Author(s)
      Deligne Clmence、Hachani Johan、Duban-Deweer Sophie、Meignan Samuel、Leblond Pierre、Carcaboso Angel M.、Sano Yasuteru、Shimizu Fumitaka、Kanda Takashi、Gosselet Fabien、Dehouck Marie-Pierre、Mysiorek Caroline
    • Journal Title

      Fluids and Barriers of the CNS

      Volume: 17 Issue: 1 Pages: 37-37

    • DOI

      10.1186/s12987-020-00198-0

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GRP78 antibodies are associated with blood-brain barrier breakdown in paraneoplastic cerebellar degeneration in Lambert-Eaton myasthenic syndrome.2020

    • Author(s)
      Shimizu F, Kanda T.
    • Journal Title

      Clin. Exp. Neuroimmunol

      Volume: 11 Issue: 2 Pages: 88-89

    • DOI

      10.1111/cen3.12575

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lambert-Eaton筋無力症とGRP78自己抗体2020

    • Author(s)
      清水 文崇, 神田 隆
    • Journal Title

      医学のあゆみ

      Volume: 274 Pages: 1299-1300

    • Related Report
      2020 Annual Research Report
  • [Journal Article] 【免疫性神経疾患update-基礎・臨床研究の最新知見-】自己免疫性神経疾患でのGRP78抗体2020

    • Author(s)
      清水 文崇, 神田 隆
    • Journal Title

      日本臨床

      Volume: 78 Pages: 1951-1956

    • Related Report
      2020 Annual Research Report
  • [Journal Article] GRP78 antibodies damage the blood-brain barrier and relate to cerebellar degeneration in Lambert-Eaton myasthenic syndrome.2019

    • Author(s)
      Shimizu F, Takeshita Y, Sano Y, Hamamoto Y, Shiraishi H, Sato T, Yoshimura S, Maeda T, Fujikawa S, Nishihara H, Kitanosono H, Tsujino A, Motomura M, Kanda T.
    • Journal Title

      Brain.

      Volume: 142 Issue: 8 Pages: 2253-2264

    • DOI

      10.1093/brain/awz168

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica2019

    • Author(s)
      Shimizu Fumitaka、Takeshita Yukio、Hamamoto Yuka、Nishihara Hideaki、Sano Yasuteru、Honda Masaya、Sato Ryota、Maeda Toshihiko、Takahashi Toshiyuki、Fujikawa Susumu、Kanda Takashi
    • Journal Title

      Annals of Clinical and Translational Neurology

      Volume: 6 Issue: 10 Pages: 2079-2087

    • DOI

      10.1002/acn3.50905

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased IP-10 production by blood-nerve barrier in multifocal acquired demyelinating sensory and motor neuropathy and multifocal motor neuropathy.2019

    • Author(s)
      Shimizu F, Oishi M, Sawai S, Beppu M, Misawa S, Matsui N, Miyashiro A, Maeda T, Takeshita Y, Nishihara H, Sano Y, Sato R, Kaji R, Kuwabara S, Kanda T.
    • Journal Title

      J Neurol Neurosurg Psychiatry

      Volume: 90 Issue: 4 Pages: 444-450

    • DOI

      10.1136/jnnp-2018-319270

    • NAID

      120006713015

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Blood-brain barrier dysfunction in immuno-mediated neurological diseases.2018

    • Author(s)
      Shimizu F, Nishihara H, Kanda T.
    • Journal Title

      Immunol Med

      Volume: 41 Issue: 3 Pages: 120-128

    • DOI

      10.1080/25785826.2018.1531190

    • Related Report
      2018 Research-status Report
  • [Presentation] 中国四国地域発で世界的に展開した学術業績 GRP78抗体とNMO この研究の発展から見えてきたこと2020

    • Author(s)
      清水文崇
    • Organizer
      第61回日本神経学会学術大会.
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Blood-brain barrier-activation in myelin oligodendrocyte glycoprotein antibody associated disorders2020

    • Author(s)
      Shimizu F, Ogawa R, Takahashi T, Takeshita Y, Misu T, Sano Y, Maeda T, Nakashima I, Fujihara K, Kanda T
    • Organizer
      第61回日本神経学会学術大会.
    • Related Report
      2020 Annual Research Report
  • [Presentation] 当院で診療したCIDP30例の臨床病型と長期経過2020

    • Author(s)
      清水 文崇, 前田 敏彦, 佐藤 亮太, 大石 真莉子, 竹下 幸男, 松尾 欣也, 佐野 泰照, 古賀 道明, 神田 隆
    • Organizer
      第31回日本末梢神経学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] MOG抗体関連疾患での血液脳関門破綻メカニズムの解明2020

    • Author(s)
      清水 文崇, 小川 諒, 原 佳那子, 門野 ちひろ, 高橋 利幸, 竹下 幸男, 三須 建郎, 佐野 泰照, 前田 敏彦, 中島 一郎, 藤原 一男, 神田 隆
    • Organizer
      第32回日本神経免疫学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 自己免疫性神経疾患から血液脳関門/血液神経関門を人為的に操作する新規標的分子の同定とその臨床応用2019

    • Author(s)
      清水文崇
    • Organizer
      第60回 日本神経学会学術大会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 血液神経関門に注目したギラン・バレー症候群患者の新規バイオマーカーの探索.2019

    • Author(s)
      清水文崇,古賀道明,藤井菜月美,竹下幸男,佐野泰照,前田敏彦,佐藤亮太,神田 隆.
    • Organizer
      第30回日本末梢神経学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 小脳性運動失調を合併したLambert-Eaton筋無力症候群患者から血液脳関門破綻に関与するGRP78抗体の同定.2019

    • Author(s)
      清水文崇,竹下幸男,佐野泰照,前田敏彦,藤川 晋,吉村俊祐,北之園寛子,白石 裕一,辻野 彰, 本村政勝,神田 隆.
    • Organizer
      第31回神経免疫学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Blood-brain barrier-activation in anti-myelin oligodendrocyte glycoprotein antibody associated disorders.2019

    • Author(s)
      Fumitaka Shimizu, Ryo Ogawa, Kanako Hara, Toshiyuki Takahashi, Yukio Takeshita, Tatsuro Misu, Yasuteru Sano, Toshihiko Maeda, Susumu Fujikawa, Ichiro Nakashima, Kazuo Fujihara, Takashi Kanda.
    • Organizer
      EctriMS 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Blood-brain barrier-activation in anti-myelin oligodendrocyte glycoprotein antibody associated disorders.2019

    • Author(s)
      Fumitaka Shimizu, Ryo Ogawa, Kanako Hara, Toshiyuki Takahashi, Yukio Takeshita, Tatsuro Misu, Yasuteru Sano, Toshihiko Maeda, Susumu Fujikawa, Ichiro Nakashima, Kazuo Fujihara, Takashi Kanda.
    • Organizer
      Sendai Conference
    • Related Report
      2019 Research-status Report
  • [Presentation] Blood-brain barrier-activation induced by immunoglobulin G in neuromyelitis optica spectrum disorder.2018

    • Author(s)
      Fumitaka Shimizu , Yuka Hamamoto, Yukio Takeshita, Yasuteru Sano, Toshihiko Maeda, Susumu Fujikawa, Masaya Honda and Takashi Kanda
    • Organizer
      日本神経学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 血液脳関門と血液神経関門を破綻させる自己免疫性神経疾患患者免疫グロブリンGの同定2018

    • Author(s)
      清水文崇,竹下幸男,古賀道明,佐野泰照,藤井菜月美,浜本優佳,前田敏彦,藤川 晋,神田 隆.
    • Organizer
      第30回神経免疫学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] ギラン・バレー症候群患者由来の免疫グロブリンGは血液神経関門を破綻させる.2018

    • Author(s)
      清水文崇,古賀道明,藤井菜月美,竹下幸男,佐野泰照,前田敏彦,神田 隆.
    • Organizer
      第29回日本末梢神経学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Identification of antibody-target from patients with central nervous system autoimmune diseases to modify the drug penetration in the blood-brain barrier.2018

    • Author(s)
      Fumitaka Shimizu, Yukio Takeshita, Yuka Hamamoto, Yasuteru Sano and Takashi Kanda.
    • Organizer
      lood-Brain Barrier - World Preclinical Congress
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Blood-brain barrier-activation induced by immunoglobulin G in multiple sclerosis.2018

    • Author(s)
      Fumitaka Shimizu, Kanako Hara, Yukio Takeshita, Yasuteru Sano, Toshihiko Maeda, Susumu Fujikawa, Masaya Honda, Ryota Sato and Takashi Kanda.
    • 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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