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A key role of the brain pericytes in the induction and development of brain inflammation under the pathophysiological conditions of obesity-associated diabetes.

Research Project

Project/Area Number 26460113
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pharmacology in pharmacy
Research InstitutionFukuoka University

Principal Investigator

TAKATA Fuyuko  福岡大学, 薬学部, 助教 (70412575)

Co-Investigator(Kenkyū-buntansha) 道具 伸也  福岡大学, 薬学部, 准教授 (60399186)
片岡 泰文  福岡大学, 薬学部, 教授 (70136513)
Research Collaborator MATSUMOTO Junichi  福岡大学, 薬学部, 助教
MACHIDA Takashi  福岡大学, 薬学部, 助教
Project Period (FY) 2014-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords脳ペリサイト / 肥満症 / TNF-alpha / トロンビン / 血液脳関門 / ミクログリア / ペリサイト / 末梢慢性炎症 / PDGFRb / PDGFRb / 肥満糖尿病 / 肥満 / 脳内炎症
Outline of Final Research Achievements

Obesity-associated diabetes is due to chronic peripheral inflammation and this is a major risk factor for brain dysfunction. However, it is unknown how the peripheral inflammation spreads to the brain to induce the central nervous system dysfunction. To address this question, we focused on brain pericytes, one of the constituents of the blood-brain barrier (BBB). Pericytes located around the microvessel are the interface between blood and brain parenchyma and have a high ability to respond to inflammatory cytokines including tumor necrosis factor (TNF)-α. In this study, we provided evidences that activated brain pericytes due to obesity-related factors such as TNF-α and thrombin have a specific property of lowering BBB function and activating microglia to develop brain inflammation under the conditions of peripheral inflammation.

Report

(5 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (15 results)

All 2018 2017 2016 2015 2014

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 1 results,  Acknowledgement Compliant: 3 results) Presentation (9 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] TNF-alpha-sensitive brain pericytes activate microglia by releasing IL-6 through cooperation between IkappaB-NFkappaB and JAK-STAT3 pathways.2018

    • Author(s)
      Matsumoto J, Dohgu S, Takata F, Machida T, Hatip FFB, Hatip-Al-Khatib I, Yamauchi A, Kataoka Y.
    • Journal Title

      Brain Research

      Volume: 1692 Pages: 34-44

    • DOI

      10.1016/j.brainres.2018.04.023

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model.2017

    • Author(s)
      Machida T, Takata F, Matsumoto J, Miyamura T, Hirata R, Kimura I, Kataoka Y, Dohgu S, Yamauchi A.
    • Journal Title

      PLoS One

      Volume: 12 Issue: 5 Pages: e0177447-e0177447

    • DOI

      10.1371/journal.pone.0177447

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of thrombin-PAR1-PKCθ/δ axis in brain pericytes in thrombin-induced MMP-9 production and blood-brain barrier dysfunction in vitro.2017

    • Author(s)
      Machida T, Dohgu S, Takata F, Matsumoto J, Kimura I, Koga M, Nakamoto K, Yamauchi A, Kataoka Y.
    • Journal Title

      Neuroscience.

      Volume: 350 Pages: 146-157

    • DOI

      10.1016/j.neuroscience.2017.03.026

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Brain pericytes are the most thrombin-sensitive matrix metalloproteinase-9-releasing cell type constituting the blood-brain barrier in vitro.2015

    • Author(s)
      3.Machida T, Takata F, Matsumoto J, Takenoshita H, Kimura I, Yamauchi A, Dohgu S, Kataoka Y
    • Journal Title

      Neurosci Lett.

      Volume: 599 Pages: 109-114

    • DOI

      10.1016/j.neulet.2015.05.028

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Brain pericyte-derived soluble factors enhance insulin sensitivity in GT1-7 hypothalamic neurons.2015

    • Author(s)
      Takahashi H, Takata F, Matsumoto J, Machida T, Yamauchi A, Dohgu S, Kataoka Y.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 457(4) Issue: 4 Pages: 532-7

    • DOI

      10.1016/j.bbrc.2015.01.016

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Tumor necrosis factor-α-stimulated brain pericytes possess a unique cytokine and chemokine release profile and enhance microglial activation.2014

    • Author(s)
      Matsumoto J, Takata F, Machida T, Takahashi H, Soejima Y, Funakoshi M, Futagami K, Yamauchi A, Dohgu S, Kataoka Y
    • Journal Title

      Neurosci Lett.

      Volume: 578 Pages: 133-8

    • DOI

      10.1016/j.neulet.2014.06.052

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] An interaction between thrombin and pericytes mediates the blood-brain barrier dysfunction in obesity-associated diabetes2017

    • Author(s)
      Fuyuko Takata, Shinya Dohgu, Takashi Machida, Junichi Matsumoto, Ikuya Kimura, Atsushi Yamauchi, Yasufumi Kataoka
    • Organizer
      12th international conference on cerebral vascular biology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] TNF-a-stimulated brain pericytes activate microglia to induce inflammation at the neurovascular unit2016

    • Author(s)
      Fuyuko Takata-Tsuji, Shinya Dohgu, Junichi Matsumoto, Ikuya Kimura, Atsushi Yamauchi, Yasufumi Kataoka
    • Organizer
      19 th international symposium on signal transduction at the Blood-Brain Barriers
    • Place of Presentation
      Copenhagen Denmark
    • Year and Date
      2016-09-14
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 脳ペリサイトのPAR1-PKCδ/θシグナルはトロンビン誘発性MMP-9産生および血液脳関門障害に関与する2016

    • Author(s)
      道具伸也、町田崇、高田芙友子、木村郁也、松本純一、山内淳史、片岡泰文
    • Organizer
      第89回日本薬理学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-03-09
    • Related Report
      2015 Research-status Report
  • [Presentation] 糖尿病によるBBB 機能不全におけるトロンビン反応性脳ペリサイトの役割2015

    • Author(s)
      町田 崇、道具 伸也、高田 芙友子、松本 純一、平田 亮介、宮村 知幸、山内 淳史、片岡 泰文
    • Organizer
      第88回日本薬理学会年会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-03-20
    • Related Report
      2014 Research-status Report
  • [Presentation] 脳ペリサイトはTNF-αに応答してグリア細胞より多量のIL-6 を遊離する。-脳ペリサイトのIL-6産生における細胞内シグナル経路の役割-2015

    • Author(s)
      松本 純一、道具 伸也、高田 芙友子、町田 崇、二神 幸次郎、山内 淳史、片岡 泰文
    • Organizer
      第88回日本薬理学会年会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-03-20
    • Related Report
      2014 Research-status Report
  • [Presentation] 脳ペリサイトはTNF-aに応答してミクログリアを活性化する2015

    • Author(s)
      高田芙友子、松本純一、道具伸也、町田崇、山内淳史、片岡泰文
    • Organizer
      第88回日本薬理学会年会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-03-20
    • Related Report
      2014 Research-status Report
  • [Presentation] TNF-α刺激により脳ペリサイトはミクログリアを活性化する2014

    • Author(s)
      高田芙友子、松本純一、道具伸也、町田崇、山内淳史、片岡泰文
    • Organizer
      第16回応用薬理シンポジウム
    • Place of Presentation
      宮城
    • Year and Date
      2014-12-04
    • Related Report
      2014 Research-status Report
  • [Presentation] TNF-αに対する脳ペリサイト応答を介するミクログリア活性化機構2014

    • Author(s)
      船越美帆、松本純一、高田芙友子、道具 伸也、町田崇、穴井佑佳、二神幸次郎、山内淳史、片岡泰文
    • Organizer
      第67回日本薬理学会西南部会
    • Place of Presentation
      福岡
    • Year and Date
      2014-11-23
    • Related Report
      2014 Research-status Report
  • [Presentation] AMPK活性化を介したメトホルミンの血液脳関門機能強化作用2014

    • Author(s)
      高田芙友子、道具伸也、松本純一、町田崇、山内淳史、片岡泰文
    • Organizer
      第3回日本くすりと糖尿病学会学術集会
    • Place of Presentation
      福岡
    • Year and Date
      2014-11-02
    • Related Report
      2014 Research-status Report

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Published: 2014-04-04   Modified: 2019-03-29  

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