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Mcrotransport of the blood-brain barrier and its application to the permeable carrier.

Research Project

Project/Area Number 18H02590
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 47060:Clinical pharmacy-related
Research InstitutionKumamoto University

Principal Investigator

OHTSUKI Sumio  熊本大学, 大学院生命科学研究部(薬), 教授 (60323036)

Co-Investigator(Kenkyū-buntansha) 伊藤 慎悟  熊本大学, 大学院生命科学研究部(薬), 准教授 (20466535)
増田 豪  熊本大学, 大学院生命科学研究部(薬), 助教 (70383940)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2020: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Keywords血液脳関門 / 脳毛細血管 / 膜タンパク質 / 輸送 / プロテオミクス / 内在化 / DDS / 脳関門
Outline of Final Research Achievements

This study aimed to elucidate the molecular mechanisms of medium and macromolecular transport systems at the blood-brain barrier and develop DDS carriers that can facilitate penetration across the blood-brain barrier. We have established methods for comprehensive analysis of internalized proteins and for isolating brain capillaries with high purity. We conducted a comparative analysis of the internalization proteome between human brain capillary endothelial cells and human umbilical vein endothelial cells, and identified blood-brain barrier-selective internalization molecules. We also identified a blood-brain barrier-permeable cyclic peptide, indicating the involvement of a new permeation mechanism. In addition, we found that the modification of the identified cyclic peptides facilitates the brain distribution of liposomes

Academic Significance and Societal Importance of the Research Achievements

本研究では脳への高分子移行に関わると考えられる脳毛細血管内皮細胞に発現する内在化分子を同定した。また、環状ペプチドの血液脳関門透過性機構としてエクソソーム分泌系の関与を明らかにした。これらの成果は血液脳関門の新たな生理機能の解明につながる事が期待される。また、同定した環状ペプチドは巨大粒子であるファージの脳移行を促進させることが従来のDDSキャリアに対する優位点である。従って、同定環状ペプチドを活用することによってナノ粒子による効率的な脳への薬物送達が可能になり、新たな中枢疾患治療薬開発に貢献することが期待される。

Report

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

    (28 results)

All 2020 2019 2018 Other

All Int'l Joint Research (3 results) Journal Article (5 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 5 results,  Open Access: 1 results) Presentation (17 results) (of which Int'l Joint Research: 7 results,  Invited: 7 results) Remarks (1 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] コシャン研究所/パリ大学(フランス)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] コシャン研究所/パリ大学(フランス)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Institut Cochin(フランス)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Novel cyclic peptides facilitating transcellular blood-brain barrier transport of macromolecules in vitro and in vivo2020

    • Author(s)
      1.Shunsuke Yamaguchi, Shingo Ito, Takeshi Masuda, Pierre-Olivier Couraud, Sumio Ohtsuki
    • Journal Title

      J Control Release

      Volume: 321 Pages: 744-755

    • DOI

      10.1016/j.jconrel.2020.03.001

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Identification of Cell-Surface Proteins Endocytosed by Human Brain Microvascular Endothelial Cells In Vitro2020

    • Author(s)
      Ito Shingo、Oishi Mariko、Ogata Seiryo、Uemura Tatsuki、Couraud Pierre-Olivier、Masuda Takeshi、Ohtsuki Sumio
    • Journal Title

      Pharmaceutics

      Volume: 12 Issue: 6 Pages: 579-579

    • DOI

      10.3390/pharmaceutics12060579

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Efficient isolation of brain capillary from a single frozen mouse brain for protein expression analysis2020

    • Author(s)
      Ogata Seiryo、Ito Shingo、Masuda Takeshi、Ohtsuki Sumio
    • Journal Title

      Journal of Cerebral Blood Flow & Metabolism

      Volume: 271678 Issue: 5 Pages: 1026-1038

    • DOI

      10.1177/0271678x20941449

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Large-Scale Quantitative Comparison of Plasma Transmembrane Proteins between Two Human Blood-Brain Barrier Model Cell Lines, hCMEC/D3 and HBMEC/cibeta.2019

    • Author(s)
      Masuda T, Hoshiyama T, Uemura T, Hirayama-Kurogi M, Ogata S, Furukawa A, Couraud PO, Furihata T, Ito S, Ohtsuki S
    • Journal Title

      Mol Pharm

      Volume: 16 Issue: 5 Pages: 2162-2171

    • DOI

      10.1021/acs.molpharmaceut.9b00114

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Changes of Blood-Brain Barrier and Brain Parenchymal Protein Expression Levels of Mice under Different Insulin-Resistance Conditions Induced by High-Fat Diet.2019

    • Author(s)
      Ogata S, Ito S, Masuda T, Ohtsuki S
    • Journal Title

      Pharm Res

      Volume: 36 Issue: 10 Pages: 141-141

    • DOI

      10.1007/s11095-019-2674-8

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] 環状ペプチドを用いた組織関門透過技術の開発2020

    • Author(s)
      伊藤慎悟
    • Organizer
      薬物動態談話会第43年会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Cyclic peptides facilitating BBB permeability of macromolecules.2019

    • Author(s)
      Sumio Ohtsuki
    • Organizer
      1st Mini-Symposium on the Blood Brain Barrier
    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 環状ペプチドを用いた組織関門透過技術の開発2019

    • Author(s)
      伊藤慎悟
    • Organizer
      第 32 回 ケミカルバイオロジー研究所セミナー 第 104 回 生物科学フロンティアセミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] バイオ医薬品の脳内送達を目指した血液脳関門における高分子物質輸送機構の解明2019

    • Author(s)
      伊藤慎悟
    • Organizer
      NanoBio第12回若手ネットワーキングシンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] Identification of cyclic peptide facilitating permeability of M13 phage across the blood-brain barrier,2019

    • Author(s)
      Shunsuke Yamaguchi, Shingo Ito, Takeshi Masuda, Sumio Ohtsuki
    • Organizer
      2019 Cerebral Vascular Biology Conference
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of cell-surface proteins internalized into in vitro human brain microvascular endothelial cells by SWATH-based quantitative proteomics.2019

    • Author(s)
      Shingo Ito, Mariko Oishi, Tatsuki Uemura, Takeshi Masuda, Tomomi Furihata, Pierre-Olivier Couraud, Sumio Ohtsuki
    • Organizer
      BBB signaling 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] オミクスの網羅的・定量的解析によって拓かれる創薬・動態研究2019

    • Author(s)
      大槻純男
    • Organizer
      薬物動態談話会 1月例会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 高分子を脳実質へ送達する血液脳関門透過性環状ペプチドの同定2019

    • Author(s)
      山口駿介、伊藤慎悟、増田豪、大槻純男
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Identification of internalized plasma membrane proteins in human brain capillary endothelial cells.2018

    • Author(s)
      Mariko Oishi, Shingo Ito, Takeshi Masuda, Tomomi Furihata, Sumio Ohtsuki
    • Organizer
      Mass Spec and Proteomics 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Comprehensive identification of internalized membrane proteins in human brain capillary endothelial cells.2018

    • Author(s)
      Mariko Oishi, Shingo Ito, Takeshi Masuda, Tomomi Furihata, Sumio Ohtsuki
    • Organizer
      The 2nd Workshop for Korea-Japan Young Scientists on Pharmaceutics
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Membrane enrichment for targeted proteomics of enzymes and transporters in different tissues and cell lines.2018

    • Author(s)
      Sumio Ohtsuki
    • Organizer
      ISSX Workshop on LC-MS Proteomics
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Identification of novel internalized cell surface proteins in human brain capillary endothelial cells by SWATH-MS2018

    • Author(s)
      Shingo Ito, Mariko Oishi, Takeshi Masuda, Tomomi Furihata, Sumio Ohtsuki
    • Organizer
      SFN2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 生体関門輸送機能を基盤とした疾患メカニズムの解明と治療への展開2018

    • Author(s)
      伊藤慎悟
    • Organizer
      第5回分子薬剤学東北セミナー
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 高分子医薬品の脳内送達に資する血液脳関門透過性環状ペプチドの同定2018

    • Author(s)
      山口駿介、伊藤慎悟、増田豪、大槻純男
    • Organizer
      第1回超分子薬剤学FGシンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] 脳内への高分子送達に資する新規BBB透過性環状ペプチドの同定2018

    • Author(s)
      山口駿介、伊藤慎悟、増田豪、大槻純男
    • Organizer
      第12回次世代を担う若手医療薬科学シンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] インスリン抵抗性マウスにおける脳関門および脳実質のタンパク質発現および機能変動の解明2018

    • Author(s)
      緒方星陵、伊藤慎悟、増田豪、大槻純男
    • Organizer
      創剤フォーラム第24回若手研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 定量プロテオミクスを活用した脳血管研究2018

    • Author(s)
      大槻純男
    • Organizer
      第2回九州血管の会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Remarks] 熊本大学大学院生命科学研究部微生物薬学分野

    • URL

      http://ohtsuki-lab.jp/

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report 2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 血液脳関門透過性ペプチド2019

    • Inventor(s)
      19.伊藤慎悟、大槻純男、山口駿介
    • Industrial Property Rights Holder
      19.伊藤慎悟、大槻純男、山口駿介
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 血液脳関門透過性ペプチド2018

    • Inventor(s)
      伊藤慎悟、大槻純男、山口駿介
    • Industrial Property Rights Holder
      伊藤慎悟、大槻純男、山口駿介
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-134042
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report

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

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