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Elucidation of the drug recognition properties and molecular entities of the organic cation-proton exchange system at the human blood-brain barrier

Research Project

Project/Area Number 16K08381
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Medical pharmacy
Research InstitutionTeikyo University

Principal Investigator

Deguchi Yoshiharu  帝京大学, 薬学部, 教授 (40254255)

Co-Investigator(Kenkyū-buntansha) 樋口 慧  帝京大学, 薬学部, 助教 (10625304)
黄倉 崇  帝京大学, 薬学部, 教授 (80326123)
Research Collaborator Kawabata Kenji  
Yamaguchi Tomoko  
Kusuhara Hiroyuki  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords血液脳関門 / トランスポーター / 有機カチオン輸送系 / 薬物認識性 / ヒト脳毛細血管モデル / ヒトiPS由来脳毛細血管内皮細胞 / プロトン-有機カチオン交換輸送系 / ヒトiPS細胞由来脳毛細血管内皮細胞 / ヒト不死化脳毛細血管内皮細胞 / 基質認識性 / 塩基性薬物 / ヒト脳移行性 / 血液脳関門モデル細胞 / ヒトiPS細胞 / ヒト血液脳関門モデル細胞 / 有機カチオン-プロトン交換輸送系 / 有機カチオントランスポーター
Outline of Final Research Achievements

To develop drugs for central disease with excellent brain transferability is an important issue for improvement of patients' QOL and reduction of medical expenses in Japan. Conventionally, the existence of a transporter (organic cation / proton (OC/H+) exchange system) that efficiently transports certain drugs into the brain has been known, but the entity has been veiled. The purpose of this study was to confirm the expression of the OC/H+ exchange system in human blood-brain barrier model and to elucidate its drug recognition properties and molecular entities. As a result, although it did not reach elucidation of the molecular entity of the OC/H+ exchange system, it was possible to clarify the drug recognition property and a screening method of this transporter.

Academic Significance and Societal Importance of the Research Achievements

超高齢社会の到来に伴い、アルツハイマー病や血管性認知症などの疾患が急増しており、これら中枢疾患に対する優れた中枢治療薬の開発が期待されている。従来からある種の薬物を脳内に効率的に運ぶトランスポーターの存在が知られていたが、その分子実体や輸送特性についてはベールに包まれていた。今回の研究において、このトランスポーターの輸送特性を明らかにすることができた。本研究成果は中枢疾患治療薬のドラッグデザインと新薬開発のブレークスルーになる可能性を秘めている。また、本研究は患者QOLの向上のみならず、我が国の医療費削減に対して大きなインパクトを与えることは間違いない。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (23 results)

All 2018 2017 2016 Other

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Acknowledgement Compliant: 3 results,  Open Access: 2 results) Presentation (14 results) (of which Int'l Joint Research: 3 results) Remarks (4 results)

  • [Journal Article] Expression and Functional Characterization of Drug Transporters in Brain Microvascular Endothelial Cells Derived from Human Induced Pluripotent Stem Cells2018

    • Author(s)
      4.Kurosawa T, Tega Y, Higuchi K, Yamaguchi T, Kawabata K, Nakakura T, Mochizuki T, Kusuhara H, Deguchi Y
    • Journal Title

      Mol Pharm.

      Volume: 15 Issue: 12 Pages: 5546

    • DOI

      10.1021/acs.molpharmaceut.8b00697

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Design, Synthesis, and Blood-Brain Barrier Transport Study of Pyrilamine Derivatives as Histone Deacetylase Inhibitors2018

    • Author(s)
      Hiranaka S, Tega Y, Higuchi K, Kurosawa T, Deguchi Y, Arata M, Ito A, Yoshida M, Nagaoka Y, Sumiyoshi T.
    • Journal Title

      ACS Med Chem Lett.

      Volume: 9 Issue: 9 Pages: 884

    • DOI

      10.1021/acsmedchemlett.8b00099

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of Proton-Coupled Organic Cation Antiporter in Varenicline Transport at Blood-Brain Barrier of Rats and in Human Brain Capillary Endothelial Cells2017

    • Author(s)
      Kurosawa T, Higuchi K, Okura T, Kobayashi K, Kusuhara H, Deguchi Y.
    • Journal Title

      J Pharm Sci.

      Volume: 106 Issue: 9 Pages: 2576

    • DOI

      10.1016/j.xphs.2017.04.032

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Histamine elimination from the cerebrospinal fluid across the blood–cerebrospinal fluid barrier: involvement of plasma membrane monoamine transporter (PMAT/SLC29A4)2016

    • Author(s)
      Usui T, Nakazawa A, Okura T, Deguchi Y, Akanuma SI, Kubo Y, Hosoya K
    • Journal Title

      J Neurochem

      Volume: 139 Issue: 3 Pages: 408

    • DOI

      10.1111/jnc.13758

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Cocktail-Dosing Microdialysis Study to Simultaneously Assess Delivery of Multiple Organic-Cationic Drugs to the Brain2016

    • Author(s)
      Atsushi Kitamura, Takashi Okura, Kei Higuchi, Yoshiharu Deguchi
    • Journal Title

      J. Pharm. Sci.

      Volume: 105 Issue: 2 Pages: 935

    • DOI

      10.1002/jps.24691

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] ヒト血液脳関門モデル細胞を用いたH+/有機カチオン交換輸送体の基質スクリーニング2018

    • Author(s)
      1.手賀悠真,北村 敦,大町蕗子,黒澤俊樹,樋口慧,板垣文雄,出口芳春
    • Organizer
      第3回トランスポーター研究会関東部会(千葉)
    • Related Report
      2018 Annual Research Report
  • [Presentation] 血液脳関門透過性を有するヒストン脱アセチル化酵素阻害剤の探索研究2018

    • Author(s)
      2.住吉孝明,平中誠弥,手賀悠真,樋口慧,黒澤俊樹,出口芳春,本間光貴,新真由美,伊藤昭博,吉田稔,長岡康夫
    • Organizer
      第36回メディシナルケミストリーシンポジウム(京都)
    • Related Report
      2018 Annual Research Report
  • [Presentation] Investigation of SLC35F2 drug transport function in mouse brain and primate BBB models.2018

    • Author(s)
      4.Tatsuki Mochizuki, Tadahaya Mizuno, Kei Higuchi, Yuma Tega, Toshiki Kurosawa, Tomoko Yamaguchi, Kenji Kawabata, Yoshiharu Deguchi, Hiroyuki Kusuhara
    • Organizer
      第33JSSX第22MDO合同年会(金沢)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Screening of proton-coupled organic cation antiporter substrates using hCMEC/D3 cells: an in vitro human blood-brain barrier model2018

    • Author(s)
      5.Atsushi Kitamura, Yuma Tega, Toshiki Kurosawa, Kei Higuchi, Yoshiharu Deguchi
    • Organizer
      第33JSSX第22MDO合同年会(金沢)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Characterization of mesoridazine transport in human cerebral microvessel endothelial cells, hCMEC/D32018

    • Author(s)
      6.Yasuyuki Debori1, Tomoko Igari, Masanori Nakakariya, Nobuyuki Amano, Yuma Tega, Kei Higuchi, Takashi Okura and Yoshiharu Deguchi
    • Organizer
      第33JSSX第22MDO合同年会(金沢)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ゲノム編集ヒト血液脳関門細胞における薬物輸送機能評価2018

    • Author(s)
      7.樋口 慧、手賀悠真、黒澤俊樹、濱弘太郎、横山和明、出口芳春
    • Organizer
      日本薬剤学会第33 年会(静岡)
    • Related Report
      2018 Annual Research Report
  • [Presentation] ヒトiPS細胞由来脳毛細血管内皮細胞におけるトランスポーターの機能的発現2018

    • Author(s)
      8.手賀悠真、黒澤俊樹、樋口 慧、山口朋子、川端健二、出口芳春
    • Organizer
      日本薬剤学会第33 年会(静岡)
    • Related Report
      2018 Annual Research Report
  • [Presentation] ヒト血液脳関門プロトン/有機カチオンアンチポーターの機能制御因子の解析2017

    • Author(s)
      樋口 慧、近藤麻美、上松祐貴、黒澤俊樹、黄倉 崇、出口芳春
    • Organizer
      日本薬学会第137年回
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] Gene expression and function of drug transporters in brain microvascular endothelial cells derived from human iPS cells2017

    • Author(s)
      Toshiki Kurosawa, Yuma Tega, Kei Higuchi, Tomoko Yamaguchi, Kenji Kawabata, Yoshiharu Deguchi
    • Organizer
      第32日本薬物動態学会年会(東京)
    • Related Report
      2017 Research-status Report
  • [Presentation] ヒトiPS由来脳毛細血管内皮細胞における薬物輸送能の解明2017

    • Author(s)
      黒澤俊樹、手賀悠真、樋口 慧、山口朋子、川端健二、出口芳春
    • Organizer
      第39回生体膜と薬物の相互作用シンポジウム(金沢)
    • Related Report
      2017 Research-status Report
  • [Presentation] H+/有機カチオン交換輸送体を標的としたHDAC阻害剤の脳へのデリバリー2017

    • Author(s)
      手賀悠真、平中誠弥、樋口慧、出口芳春、伊藤昭博、吉田稔、長岡康夫、住吉孝明
    • Organizer
      第39回生体膜と薬物の相互作用シンポジウム(金沢)
    • Related Report
      2017 Research-status Report
  • [Presentation] CRISPR-Cas9システムを用いたヒト血液脳関門細胞の排出輸送系ノックアウト2017

    • Author(s)
      樋口 慧、手賀悠真、黒澤俊樹、濱弘太郎、横山和明、出口芳春
    • Organizer
      日本薬学会第137年回 (仙台)
    • Related Report
      2017 Research-status Report
  • [Presentation] 血液脳関門におけるバレニクリンの輸送解析2016

    • Author(s)
      樋口 慧、黒澤俊樹、黄倉 崇、楠原洋之、出口芳春
    • Organizer
      第38回生体膜と薬物の相互作用シンポジウム(名古屋)
    • Place of Presentation
      名古屋
    • Year and Date
      2016-11-17
    • Related Report
      2016 Research-status Report
  • [Presentation] Transport characteristics of varenicline in the blood-brain barrier2016

    • Author(s)
      Toshiki Kurosawa, Kei Higuchi, Takashi Okura, Hiroyuki Kusuhara, and Yoshiharu Deguchi
    • Organizer
      第31日本薬物動態学会年会(松本)
    • Place of Presentation
      松本
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Remarks] 帝京大学薬学部 -薬物動態学研究室 論文リスト

    • URL

      http://www.pharm.teikyo-u.ac.jp/

    • Related Report
      2018 Annual Research Report
  • [Remarks] researchmap

    • URL

      https://researchmap.jp/read0070655/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 帝京大学薬学部

    • URL

      http://www.pharm.teikyo-u.ac.jp

    • Related Report
      2017 Research-status Report
  • [Remarks] 帝京大学薬学部

    • URL

      http://www.pharm.teikyo-u.ac.jp/

    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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