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Novel strategy for the development of therapeutics against autoimmune disease of the central nervous system, utilizing the crosstalk of cells forming blood-brain barrier.

Research Project

Project/Area Number 17H04197
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionYamaguchi University

Principal Investigator

KANDA Takashi  山口大学, 大学院医学系研究科, 教授 (40204797)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2017: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
Keywords血液脳関門 / ペリサイト / 内皮細胞 / 低分子化合物 / アストロサイト / 脂質メディエーター / ぺリサイト / 免疫 / 薬物送達 / 脳神経疾患
Outline of Final Research Achievements

Twenty selective lipid mediator receptor agonists, screened to be permeable through blood-brain barrier (BBB), were analyzed. After adding in the culture media for BBB multi-culture model composed of human endothelial cell, pericyte and astrocyte, upregulation of BDNF in aliquot was observed in two compounds, EP4 agonist and S1P5 agonist. Since these two compounds also increase the production of BDNF in astrocyte monoculture, we concluded that they may go through endothelial cell/pericyte layer, and affect astrocyte directly to enhance the production of BDNF.

Academic Significance and Societal Importance of the Research Achievements

今回同定した2種類の脂溶性化合物は、中枢神経内での神経栄養因子の産生を促すことによって中枢神経実質の内部環境を神経再生の方向に改変する神経変性疾患治療薬のリード化合物としての可能性があるだけでなく、BBB調節のための栄養因子の分泌を人為的に制御できる可能性があり、高分子治療薬を中枢神経内に流入させる際の補助治療薬となりうると考えられた。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (24 results)

All 2019 2018 2017

All Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (18 results) (of which Int'l Joint Research: 5 results,  Invited: 7 results)

  • [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 Annual Research 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
      2019 Annual Research Report
    • Peer Reviewed
  • [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 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fingolimod promotes blood-nerve barrier properties in vitro2018

    • Author(s)
      Nishihara Hideaki、Maeda Toshihiko、Sano Yasuteru、Ueno Maho、Okamoto Nana、Takeshita Yukio、Shimizu Fumitaka、Koga Michiaki、Kanda Takashi
    • Journal Title

      Brain and Behavior

      Volume: 8 Issue: 4

    • DOI

      10.1002/brb3.924

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A perfused human blood-brain barrier on-a-chip for high throughoutput assessment of barrier function and antibody transport.2018

    • Author(s)
      Nienke R Wevers, Dhanesh G Kasi, Taylor Gray, Karlijn J Wilschut, Benjamin Smith, Remko van Vught, Fumitaka Shimizu, Yasuteru Sano, Takashi Kanda, Graham Marsh, Sebastiaan J Trietsch, Paul Vulto, Henriette L Lanz, Birgit Obermeier
    • Journal Title

      Fluids Barriers CNS

      Volume: 15 Issue: 1 Pages: 23-23

    • DOI

      10.1186/s12987-018-0108-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica.2017

    • Author(s)
      Fumitaka Shimizu, Kritin L. Schaller, Gregory P. Owens, Anne C. Cotleur, Debra Kellner, Yukio Takeshita, Birgit Obermeier, Thomas J. Kryzer, Yasuteru Sano, Takashi Kanda, Vanda A. Lennon, Richard M. Ransohoff, Jeffrey L. Bennett
    • Journal Title

      SciTransl Med

      Volume: 9 Issue: 397 Pages: 49-53

    • DOI

      10.1126/scitranslmed.aai9111

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] シンポジウム:「神経免疫疾患の病態解明への多面的アプローチ」血液脳関門からのアプローチ2019

    • Author(s)
      神田 隆
    • Organizer
      第60回日本神経学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 血液脳関門の人為的操作:中枢神経疾患の新しい治療へ2019

    • Author(s)
      神田 隆
    • Organizer
      第60回日本神経学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 神経免疫疾患治療の進歩.シンポジウム1 「自己免疫疾患治療の進歩 平成から令和へ」2019

    • Author(s)
      神田 隆
    • Organizer
      第47回日本臨床免疫学会総会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 教育講演:神経系を侵す自己免疫疾患2019

    • Author(s)
      神田 隆
    • Organizer
      第47回日本臨床免疫学会総会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [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 2019
    • Related Report
      2019 Annual Research 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 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The effect of Neuromyelitis Optica (NMO)-IgG and anti-IL-6 receptor monoclonal antibody (SA237;satralizumab) for barrier function at the Blood-Brain Barrier in vitro2019

    • Author(s)
      Yukio Takeshita, Kenichi Serizawa, Susumu Fujikawa, Fumitaka Shimizu, Toshihiko Maeda, Yasuteru Sano, Michiaki Koga, Takashi Kanda
    • Organizer
      第60回日本神経学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] The effect of Neuromyelitis Optica (NMO)-IgG and anti-IL-6 receptor monoclonal antibody (SA237;satralizumab) for barrier function at the Blood-Brain Barrier in vitro2019

    • Author(s)
      Yukio Takeshita, Kenichi Serizawa, Susumu Fujikawa, Fumitaka Shimizu, Toshihiko Maeda, Yasuteru Sano, Michiaki Koga, Takashi Kanda
    • Organizer
      ECTRIMS 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of targeted membrane antigens of human brain microvascular endothelial cells in relapsing-remitting multiple sclerosis.2019

    • Author(s)
      Yukio Takeshita, Susumu Fujikawa, Tomohiro Makino, Masato Hoshino, Takeshi Hanada, Makoto Masumura, Hideaki Nishihara, Toshihiko Maeda, Fumitaka Shimizu, Yasuteru Sano, Michiaki Koga, Takashi Kanda
    • Organizer
      XXIV World Congress of Neurology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] BBB構成細胞による継時的バリア評価モデルの開発とIL-6受容体阻害が視神経脊髄炎のBBB破綻に与える効果検証2019

    • Author(s)
      竹下幸男, 芹澤賢一, 藤川 晋, 清水文崇, 藤澤美和子, 古賀道明, 神田 隆
    • Organizer
      第31回日本神経免疫学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] The barrier effect of the components of the blood-brain barrier and the blood-nerve barrier in vitro.2018

    • Author(s)
      Takeshita Y, Fujikawa S, Shimizu F, Maeda T, Sano Y, Koga M, Kanda T.
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Construction of the new multi-cultured in vitro blood-brain barrier model under shear forces.2018

    • Author(s)
      Fujikawa S, Takeshita Y, Maeda T, Shimizu F, Sano Y, Kanda T.
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 再発寛解型多発性硬化症における微小脳血管膜蛋白に対する標的抗原分子の同定法の確立2018

    • Author(s)
      竹下幸男,藤川 晋,牧野智宏,星野将人,花田雄志,升村 誠,西原秀昭,前田敏彦,清水文崇,佐野泰照,古賀道明,神田 隆
    • Organizer
      第30回神経免疫学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The new in vitro blood-brain barrier (BBB) model under shear forces with multi-culture of BBB components in multiple sclerosis.2018

    • Author(s)
      Takeshita Y, Fujikawa S, Maeda T, Shimizu F, Sano Y, Kanda T.
    • Organizer
      34th Congress of ECTRIMS 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Destruction and repair of blood-brain barrier in neuroimmunological disoders2018

    • Author(s)
      Kanda T
    • Organizer
      第41回日本神経科学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 神経系のバリアー機能とその分子構造2018

    • Author(s)
      神田 隆
    • Organizer
      第30回日本神経免疫学会学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 血液脳関門・血液末梢神経関門モデルからの創薬2018

    • Author(s)
      神田 隆
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] The effect of blood-brain barrier (BBB)-specific laminins for barrier function with a new in vitro BBB model incorporating multi-culturing system of BBB components.2017

    • Author(s)
      Takeshita Y, Fujikawa S, Shimizu F, Sano Y, Maeda T, Kanda T
    • Organizer
      23rd World Congress of Neurology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2021-02-19  

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