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Brain-targeting of exosomes based on the virus receptors-mediated transport at the human blood-brain barrier

Research Project

Project/Area Number 19H03390
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 InstitutionThe University of Tokushima

Principal Investigator

TACHIKAWA Masanori  徳島大学, 大学院医歯薬学研究部(薬学域), 教授 (00401810)

Co-Investigator(Kenkyū-buntansha) 船本 健一  東北大学, 流体科学研究所, 准教授 (70451630)
福田 達也  和歌山県立医科大学, 薬学部, 講師 (90805160)
Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2021: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2020: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords血液脳関門 / エクソソーム / 輸送系 / 細胞外小胞 / 脳微小血管網 / 三次元脳血管網 / 微小環境 / 薬物送達 / 三次元血管網 / 脳細胞標的化
Outline of Research at the Start

近年開発が進む高分子中枢薬の、脳への薬物送達を実現するためには、脳毛細血管内皮細胞を実体とする血液脳関門(Blood-Brain Barrier, BBB)の透過技術に加え、神経細胞やグリア細胞への輸送標的化の基盤技術開発が重要である。本研究は、エクソソーム受容体を介するBBBエクソソーム突破機構をヒトに特化して解明し、その知見を基に、BBB透過・脳細胞への輸送標的化機能を備えた人工エクソソームの創製を目指す。

Outline of Final Research Achievements

This research project aims to unveil the exosomes transport systems at the human blood-brain barrier and to establish the basis of the blood-brain barrier-permeable and central nervus systems-targeting drug carriers development. We have done the protein profiling of exosomes by comprehensive proteomics, the clarification of exosomes transport mechanisms in human brain microvessel endothelial cells as well as the construction of three-dimensional model of brain microvasculature as an evaluation tool of the blood-brain barrier exosomes transport.

Academic Significance and Societal Importance of the Research Achievements

高分子性中枢疾患治療薬の脳への効率的な薬物送達を実現するためには、血液脳関門突破の方法論の確立に加え脳実質細胞への輸送標的化の技術開発が不可欠である。本研究は、がん細胞などから放出されるエクソソームとウイルスの細胞膜透機構における類似性に基づいて、エクソソームがもつ血液脳関門透過能と脳細胞への輸送標的化能の仕組みに迫るという学術的意義がある。さらに脳への送達に不可欠なドラッグキャリアの開発基盤が創造されるという社会的意義がある。

Report

(4 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (17 results)

All 2022 2021 2020 2019

All Journal Article (3 results) (of which Peer Reviewed: 3 results) Presentation (14 results) (of which Int'l Joint Research: 4 results,  Invited: 4 results)

  • [Journal Article] Distinct Transport Properties of Human Pannexin 1 and Connexin 32 Hemichannels.2020

    • Author(s)
      Tachikawa M, Akaogi R, Taii A, Akanuma SI, Uchida Y, Terasaki T.
    • Journal Title

      J Pharm Sci.

      Volume: 109(3) Issue: 3 Pages: 1395-1402

    • DOI

      10.1016/j.xphs.2019.12.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Polarized hemichannel opening of pannexin 1/connexin 43 contributes to dysregulation of transport function in blood-brain barrier endothelial cells2020

    • Author(s)
      Tachikawa Masanori、Murakami Koji、Akaogi Ryo、Akanuma Shin-ichi、Terasaki Tetsuya、Hosoya Ken-ichi
    • Journal Title

      Neurochemistry International

      Volume: 132 Pages: 104600-104600

    • DOI

      10.1016/j.neuint.2019.104600

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Targeted Proteomics-Based Quantitative Protein Atlas of Pannexin and Connexin Subtypes in Mouse and Human Tissues and Cancer Cell Lines.2020

    • Author(s)
      Tachikawa M, Kaneko Y, Ohtsuki S, Uchida Y, Watanabe M, Ohtsuka H, Terasaki T.
    • Journal Title

      J Pharm Sci.

      Volume: 109(2) Issue: 2 Pages: 1161-1168

    • DOI

      10.1016/j.xphs.2019.09.024

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] マイクロ流体デバイスを用いた三次元ヒト脳微小血管網の構築2022

    • Author(s)
      佐藤桃子、稲垣舞、酒巻祐花、船本健一、立川正憲
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ヒト血液脳関門における細胞外小胞輸送システムの多様性と特異性2022

    • Author(s)
      立川正憲
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Reconstruction of perfusable human 3D microvasculature on a chip as an evaluation model of cancer cell extravasation and drug transport2021

    • Author(s)
      Sakamaki Y, Inagaki M, Sato M, Funamoto K, Tachikawa M
    • Organizer
      Eighteenth International Conference on Flow Dynamics
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Reconstruction of 3D human brain microvasculature on a chip using brain endothelial cells, astrocytes and pericytes2021

    • Author(s)
      Sato M, Inagaki M, Sakamaki Y, Funamoto K, Tachikawa M
    • Organizer
      Eighteenth International Conference on Flow Dynamics
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 網羅的プロテオミクスを用いたヒト脳毛細血管内皮細胞への内在化活性を示す脳転移性メラノーマSK-Mel-28由来細胞外小胞の特性解析2021

    • Author(s)
      木下暢、大野大樹、小迫英尊、稲垣舞、立川正憲
    • Organizer
      日本薬剤学会第36年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 定量プロテオミクスが拓いた脳関門物流システム-Brain Barrier Logistics-解明研究2021

    • Author(s)
      立川正憲
    • Organizer
      第14回日本薬物動態学会ショートコース
    • Related Report
      2021 Annual Research Report
  • [Presentation] 定量プロテオミクス解析から見えてきた中枢-免疫インターフェースとしての血液脳関門の役割2021

    • Author(s)
      立川正憲
    • Organizer
      第44回日本神経科学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ヒト胎盤絨毛細胞株BeWo細胞由来エクソソームのヒト脳血管内皮細胞 (hCMEC/D3)への内在化2021

    • Author(s)
      稲垣舞,佐野陽乃里,中野瑛介,登美斉俊,立川正憲
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 3D Human Blood-Brain Barrier Chip for Central Nervous System Drug Development2020

    • Author(s)
      Sato M,Sakamaki Y,Inagaki M,Funamoto K,Tachikawa M
    • Organizer
      Seventeenth International Conference on Flow Dynamics
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 定量プロテオミクスで解き明かす血液脳関門・血液くも膜関門2020

    • Author(s)
      立川正憲
    • Organizer
      第39回日本認知症学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] The human-specific virus receptor CD46 makes a major contribution to the internalization of brain-metastatic melanoma-derived exosomes by human blood-brain barrier endothelial cells.2019

    • Author(s)
      Tachikawa M, Kuroda H, Watanabe M, Uchida Y, Terasaki T
    • Organizer
      13th International Conference of Cerebral Vascular Biology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Blood-brain barrier-permeable proteins and transport characteristics in brain endothelial cells2019

    • Author(s)
      Tachikawa M, Terasaki T
    • Organizer
      日本薬物動態学会第34年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 中枢関門科学:Connecting the human dots2019

    • Author(s)
      立川正憲
    • Organizer
      第13回次世代を担う若手医療薬科学シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 定量プロテオミクスを基軸とする「脳関門中枢創薬科学」の新たな展開2019

    • Author(s)
      立川正憲
    • Organizer
      第41回神経組織培養研究会
    • Related Report
      2019 Annual Research Report
    • Invited

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Published: 2019-04-18   Modified: 2024-01-30  

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