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A novel technology for regulating blood brain barrier

Research Project

Project/Area Number 17K19487
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Research Field Pharmaceutical Sciences and related fields
Research InstitutionOsaka University

Principal Investigator

Okada Yoshiaki  大阪大学, 薬学研究科, 准教授 (50444500)

Co-Investigator(Kenkyū-buntansha) 樋野 展正  大阪大学, 薬学研究科, 助教 (90469916)
Research Collaborator KONDOH masuo  
TAKEDA hiroyuki  
Project Period (FY) 2017-06-30 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywords血液脳関門 / Claudin-5 / 抗体 / 血管内皮細胞 / 薬学 / DDS / 血管生物学
Outline of Final Research Achievements

The blood-brain barrier function of the cerebrovascular system protects the brain by preventing foreign matter from entering the brain. On the other hand, the blood-brain barrier also hinders the transfer of drugs to the brain, which hinders the development of drugs for treating brain diseases. In this study, we aimed to develop a technology to temporarily loosen the blood-brain barrier for the effective drug delivery to the brain. Since the blood-brain barrier is generated by tight junction of vascular endothelial cells, we generated anti-human Claudin-5 antibodies that inhibit the junction. In addition, in order to evaluate the blood-brain barrier control activity of these antibodies, we generated mice having human Claudin-5 and obtained data suggesting that the anti-Claudin-5 antibodies have the activity of loosening the blood-brain barrier.

Academic Significance and Societal Importance of the Research Achievements

高齢化社会の我が国ではアルツハイマー病など脳疾患の患者が増加の一途を辿っている。製薬企業の努力にもかかわらず、脳疾患治療薬の開発が難航する理由の一つに、薬の脳移行を妨げる血液脳関門の存在がある。本来、血液脳関門は、脳を異物侵入から守る生体防御機構であるが、脳疾患の薬の脳への移行も阻害してしまうため、優れた治療薬の候補分子が、脳に移行しないという理由で薬にならないという現状がある。我々の今回の研究は、血液脳関門を緩め、脳に効率よく薬を届ける技術の開発研究であり、今後の脳疾患治療薬開発に貢献すると期待される。

Report

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

    (25 results)

All 2019 2018 2017 Other

All Journal Article (12 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 12 results,  Open Access: 3 results) Presentation (12 results) (of which Int'l Joint Research: 3 results,  Invited: 4 results) Remarks (1 results)

  • [Journal Article] Endothelial cell-specific gene expression induced by transcription factors and epigenetics2019

    • Author(s)
      岡田 欣晃
    • Journal Title

      生化学

      Volume: 91 Issue: 1 Pages: 96-100

    • DOI

      10.14952/SEIKAGAKU.2019.910096

    • NAID

      40021833046

    • ISSN
      0037-1017
    • Year and Date
      2019-02-25
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires Hes1 to bind diverse DNA sites2019

    • Author(s)
      Noguchi Yu-taro、Nakamura Miki、Hino Nobumasa、Nogami Jumpei、Tsuji Sayaka、Sato Takahiko、Zhang Lidan、Tsujikawa Kazutake、Tanaka Toru、Izawa Kohei、Okada Yoshiaki、Doi Takefumi、Kokubo Hiroki、Harada Akihito、Uezumi Akiyoshi、Gessler Manfred、Ohkawa Yasuyuki、Fukada So-ichiro
    • Journal Title

      Development

      Volume: 146 Issue: 4 Pages: 163618-163618

    • DOI

      10.1242/dev.163618

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Lipin-1 is a novel substrate of protein phosphatase PGAM52019

    • Author(s)
      Okuno Hiroko、Okuzono Haruna、Hayase Ayaka、Kumagai Fumiko、Tanii Shohei、Hino Nobumasa、Okada Yoshiaki、Tachibana Keisuke、Doi Takefumi、Ishimoto Kenji
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 509 Issue: 4 Pages: 886-891

    • DOI

      10.1016/j.bbrc.2019.01.031

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Anti-Claudin Antibodies as a Concept for Development of Claudin-Directed Drugs2018

    • Author(s)
      Hashimoto Yosuke、Okada Yoshiaki、Shirakura Keisuke、Tachibana Keisuke、Sawada Makoto、Yagi Kiyohito、Doi Takefumi、Kondoh Masuo
    • Journal Title

      Journal of Pharmacology and Experimental Therapeutics

      Volume: 368 Issue: 2 Pages: 179-186

    • DOI

      10.1124/jpet.118.252361

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation2018

    • Author(s)
      Shirakura Keisuke、Ishiba Ryosuke、Kashio Taito、Funatsu Risa、Tanaka Toru、Fukada So-ichiro、Ishimoto Kenji、Hino Nobumasa、Kondoh Masuo、Ago Yukio、Fujio Yasushi、Yano Kiichiro、Doi Takefumi、Aird William C.、Okada Yoshiaki
    • Journal Title

      Journal of Cell Science

      Volume: 132 Pages: 220228-220228

    • DOI

      10.1242/jcs.220228

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pancreatic adenocarcinoma upregulated factor has oncogenic functions in oral squamous cell carcinoma2018

    • Author(s)
      Sasahira T, Kurihara M, Nishiguchi Y, Nakashima C, Kirita T, Kuniyasu H.
    • Journal Title

      Histopathol

      Volume: 70 Pages: 539-548

    • DOI

      10.1016/j.ejps.2018.02.016

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] ETV2-TET1/TET2 Complexes Induce Endothelial Cell-Specific Robo4 Expression via Promoter Demethylation.2018

    • Author(s)
      Tanaka Toru、Izawa Kohei、Maniwa Yusuke、Okamura Maki、Okada Atsumasa、Yamaguchi Tomoko、Shirakura Keisuke、Maekawa Naoki、Matsui Hayato、Ishimoto Kenji、Hino Nobumasa、Nakagawa Osamu、Aird William C.、Mizuguchi Hiroyuki、Kawabata Kenji、Doi Takefumi、Okada Yoshiaki
    • Journal Title

      Sci Rep.

      Volume: 8(1) Issue: 1 Pages: 5653-5653

    • DOI

      10.1038/s41598-018-23937-8

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Endothelial Robo4 regulates IL-6 production by endothelial cells and monocytes via a crosstalk mechanism in inflammation2018

    • Author(s)
      Shirakura Keisuke、Ishiba Ryosuke、Kashio Taito、Sakai Miki、Fukushima Yu、Yamamoto Nana、Manabe Shiori、Shigesada Naoya、Tanaka Toru、Hino Nobumasa、Aird William C.、Doi Takefumi、Okada Yoshiaki
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 495 Issue: 1 Pages: 801-806

    • DOI

      10.1016/j.bbrc.2017.11.067

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Creation of a Claudin-2 Binder and Its Tight Junction?Modulating Activity in a Human Intestinal Model2017

    • Author(s)
      Takigawa Mutsumi、Iida Manami、Nagase Shotaro、Suzuki Hidehiko、Watari Akihiro、Tada Minoru、Okada Yoshiaki、Doi Takefumi、Fukasawa Masayoshi、Yagi Kiyohito、Kunisawa Jun、Kondoh Masuo
    • Journal Title

      J Pharmacol Exp Ther.

      Volume: 363 Issue: 3 Pages: 444-451

    • DOI

      10.1124/jpet.117.242214

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Claudin-5-Binders Enhance Permeation of Solutes across the Blood-Brain Barrier in a Mammalian Model2017

    • Author(s)
      Hashimoto Yosuke、Shirakura Keisuke、Okada Yoshiaki、Takeda Hiroyuki、Endo Kohki、Tamura Maki、Watari Akihiro、Sadamura Yoshifusa、Sawasaki Tatsuya、Doi Takefumi、Yagi Kiyohito、Kondoh Masuo
    • Journal Title

      J Pharmacol Exp Ther.

      Volume: 363 Issue: 2 Pages: 275-283

    • DOI

      10.1124/jpet.117.243014

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Angubindin-1, a novel paracellular absorption enhancer acting at the tricellular tight junction.2017

    • Author(s)
      Krug SM, Hayaishi T, Iguchi D, Watari A,Takahashi A, Fromm M, Nagahama M, Takeda H, Okada Y,Sawasaki T, Doi T, Yagi K, Kondoh M
    • Journal Title

      J. Control. Release.

      Volume: 260 Pages: 1-11

    • DOI

      10.1016/j.jconrel.2017.05.024

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Degradation of human Lipin-1 by BTRC E3 ubiquitin ligase2017

    • Author(s)
      Ishimoto Kenji、Hayase Ayaka、Kumagai Fumiko、Kawai Megumi、Okuno Hiroko、Hino Nobumasa、Okada Yoshiaki、Kawamura Takeshi、Tanaka Toshiya、Hamakubo Takao、Sakai Juro、Kodama Tatsuhiko、Tachibana Keisuke、Doi Takefumi
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 488 Issue: 1 Pages: 159-164

    • DOI

      10.1016/j.bbrc.2017.04.159

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] 脳内に効率よく薬を運ぶための新しい血液脳関門制御技術2019

    • Author(s)
      岡田 欣晃
    • Organizer
      大阪大学 新技術説明会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] HDAC阻害剤MS-275のガン転移モデルにおける二面性2019

    • Author(s)
      岡田 欣晃
    • Organizer
      第5回血管生物若手研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 炎症時の血管透過性を制御するRobo4-TRAF7シグナルの解析2019

    • Author(s)
      小西 博尭
    • Organizer
      第5回血管生物若手研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 血管内皮細胞特異的タンパク質Robo4による炎症血管の透過性制御2019

    • Author(s)
      岡田 欣晃
    • Organizer
      薬学会第139年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ETV2-TET1/2 Complexes Induce Endothelial Cell-Specific Robo4 Expression via Promoter Demethylation2018

    • Author(s)
      Tor Tanaka, Kohei Izawa, Osamu Nakagawa, William C. Aird, Hiroyuki Mizuguchi, Kenji Kawabata, Takefumi Doi, Yoshiaki Okada
    • Organizer
      The 20th International Vacular Biology Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Keisuke Shirakura, Ryosuke Ishiba, Taito Kashio, Risa Funatsu, William C. Aird, Takefumi Doi, Yoshiaki Okada2018

    • Author(s)
      Robo4 and its novel binding protein TRAF7 suppress vascular hyperpermeability in inflammation
    • Organizer
      The 20th International Vacular Biology Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 血管内皮細胞を生み出すエピジェネティクス機構とは?2018

    • Author(s)
      岡田 欣晃
    • Organizer
      第13回 関西バイオ創薬研究会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 血管内皮細胞特異的な遺伝子発現を生み出す転写・エピジェネティック因子複合体2018

    • Author(s)
      岡田欣晃
    • Organizer
      阪大医学系研究科若手研究フォーラム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ETV2, an endothelial master transcription factor, induces endothelial cell-specific gene expression via promoter demethylation.2018

    • Author(s)
      Toru Tanaka, Kohei Izawa, Osamu Nakagawa, William C. Aird, Hiroyuki Mizuguchi, Kenji Kawabata, Takefumi Doi, Yoshiaki Okada
    • Organizer
      The 16th Korea-Japan Joint Symposium on Vascular Bioloty
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 血管内皮細胞特異的膜タンパク質Robo4の炎症における役割2018

    • Author(s)
      白倉圭佑, 樫尾泰斗, 船津梨彩, William Aird, 土井健史, 岡田欣晃
    • Organizer
      CVMW2018心血管代謝週間
    • Related Report
      2018 Annual Research Report
  • [Presentation] 1.新規内皮細胞特異的複合体Robo4-TRAF7は炎症時の血管透過性亢進を抑制する2017

    • Author(s)
      白倉圭佑, 石破亮祐, 樫尾泰斗, 船津梨彩, William C Aird, 岡田欣晃, 土井健史
    • Organizer
      第25回日本血管生物医学会学術集会/心血管代謝週間
    • Related Report
      2017 Research-status Report
  • [Presentation] 2.血管内皮細胞特異的受容体Robo4が癌の増殖、転移、血管透過性に与える影響の解析2017

    • Author(s)
      石破亮祐, 樫尾泰斗, 吉岡靖雄, 鈴木亮, 小山正平, 青枝大貴, 岡田欣晃, 土井健史
    • Organizer
      第25回日本血管生物医学会学術集会/心血管代謝週間
    • Related Report
      2017 Research-status Report
  • [Remarks] 大阪大学大学院薬学研究科 生命情報解析学分野

    • URL

      https://seimeijohokaiseki.wixsite.com/tanpaku

    • Related Report
      2018 Annual Research Report

URL: 

Published: 2017-07-21   Modified: 2020-03-30  

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