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miRNAがヒストン修飾の変化を介して動脈硬化を進展させる機序の解明

Research Project

Project/Area Number 17J07088
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section国内
Research Field Applied pharmacology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

東島 佳毅  東京医科歯科大学, 難治疾患研究所, 特別研究員(PD)

Project Period (FY) 2017-04-26 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords動脈硬化 / miRNA / 炎症性遺伝子 / ヒストン修飾 / 接着因子
Outline of Annual Research Achievements

申請者は採用期間初年度(平成29年度)に動脈硬化に寄与する新規miRNAを複数同定した。翌平成30年度は同定した新規miRNAの標的遺伝子探索を行い、動脈硬化に寄与する新規miRNAが共通してヒストン修飾酵素を標的とすることを見出した。最終年度となる令和元年度は、これまでの研究で見出したヒストン修飾酵素の血管内皮細胞における機能について、生化学および薬理学的手法を用いてより詳細に解析を行った。その結果、正常時の血管内皮細胞ではヒストン修飾酵素が協調的に働き炎症性遺伝子の発現を抑制していること、またこれらヒストン修飾酵素による遺伝子発現抑制機構の破綻が炎症性遺伝子の転写活性化および動脈硬化初期病巣形成に関与する可能性が示唆された。現在、ヘテロ二本鎖核酸と呼ばれる新規人工機能核酸を用いて、血管内皮細胞特異的にヒストン修飾酵素の発現を制御する手法の開発に取り組んでおり、血管内細胞特異的に発現するCD31やVE-Cadherinに対する抗体をヘテロ二本鎖核酸に結合させることで、血管内細胞特異的なヘテロ二本鎖核酸の輸送を試みている。in vitroおよび野生型マウスにおいて血管内皮細胞特異的なヘテロ二本鎖核酸の輸送を確認した後、最終的には動脈硬化モデルであるApoE欠損マウスにヘテロ二本鎖核酸を投与し血管内細胞特異的にヒストン修飾酵素の発現を制御することで、実際の生体においてヒストン修飾酵素が動脈硬化の発症および進展に関与するかどうかについて検討する予定である。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Report

(3 results)
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (21 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (2 results) Journal Article (8 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 6 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (11 results) (of which Int'l Joint Research: 3 results,  Invited: 2 results)

  • [Int'l Joint Research] UCSD(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] カリフォルニア大学サンディエゴ校(米国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells2020

    • Author(s)
      Higashijima Y, Matsui Y, Shimamura T, Nakaki R, Nagai N, Tsutsumi S, Abe Y, Link VM, Osaka M, Yoshida M, Watanabe R, Tanaka T, Taguchi A, Miura M, Ruan X, Li G, Inoue T, Nangaku M, Kimura H, Furukawa T, Aburatani H, Wada Y, Ruan Y, Glass CK, Kanki Y
    • Journal Title

      The EMBO Journal

      Volume: 39 Issue: 7 Pages: 1-1

    • DOI

      10.15252/embj.2019103949

    • NAID

      120006902140

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular mechanistic insights: The emerging role of SOXF transcription factors in tumorigenesis and development2019

    • Author(s)
      Higashijima Yoshiki、Kanki Yasuharu
    • Journal Title

      Seminars in Cancer Biology

      Volume: - Pages: 39-48

    • DOI

      10.1016/j.semcancer.2019.09.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lysine demethylase 7a regulates the anterior-posterior development in mouse by modulating the transcription of Hox gene cluster2019

    • Author(s)
      Higashijima Yoshiki、Nagai Nao、Kitazawa Taro、Kawamura Yumiko、Taguchi Akashi、Nakada Natsuko、Nangaku Masaomi、Furukawa Tetsushi、Aburatani Hiroyuki、Kurihara Hiroki、Wada Youichiro、Kanki Yasuharu
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/707125

    • Related Report
      2019 Annual Research Report
    • Open Access
  • [Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells2018

    • Author(s)
      Higashijima Y, Matsui Y, Shimamura T, Tsutsumi S, Nakaki R, Abe Y, Link VM, Osaka M, Yoshida M, Watanabe R, Tanaka T, Taguchi A, Miura M, Inoue T, Nangaku M, Kimura H, Furukawa T, Aburatani H, Wada Y, Glass CK, Kanki Y
    • Journal Title

      bioRxiv

      Volume: - Pages: 456491-456491

    • DOI

      10.1101/456491

    • NAID

      120006902140

    • Related Report
      2018 Annual Research Report
    • Open Access / Int'l Joint Research
  • [Journal Article] Sodium glucose cotransporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice2018

    • Author(s)
      Tanaka Shinji、Sugiura Yuki、Saito Hisako、Sugahara Mai、Higashijima Yoshiki、Yamaguchi Junna、Inagi Reiko、Suematsu Makoto、Nangaku Masaomi、Tanaka Tetsuhiro
    • Journal Title

      Kidney International

      Volume: 94 Issue: 5 Pages: 912-925

    • DOI

      10.1016/j.kint.2018.04.025

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Persistent expression of neutrophil gelatinase-associated lipocalin and M2 macrophage markers and chronic fibrosis after acute kidney injury2018

    • Author(s)
      Saito Hisako、Tanaka Tetsuhiro、Tanaka Shinji、Higashijima Yoshiki、Yamaguchi Junna、Sugahara Mai、Ito Marie、Uchida Lisa、Hasegawa Sho、Wakashima Takeshi、Fukui Kenji、Nangaku Masaomi
    • Journal Title

      Physiological Reports

      Volume: 6 Issue: 10 Pages: e13707-e13707

    • DOI

      10.14814/phy2.13707

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Applications of the CRISPR-Cas9 system in kidney research2017

    • Author(s)
      Higashijima Yoshiki、Hirano Seiichi、Nangaku Masaomi、Nureki Osamu
    • Journal Title

      Kidney International

      Volume: 92 Issue: 2 Pages: 324-335

    • DOI

      10.1016/j.kint.2017.01.037

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury.2017

    • Author(s)
      Tanaka S, Tanaka T, Kawakami T, Takano H, Sugahara M, Saito H, Higashijima Y, Yamaguchi J, Inagi R, Nangaku M.
    • Journal Title

      Kidney Int

      Volume: 印刷中 Issue: 1 Pages: 154-164

    • DOI

      10.1016/j.kint.2017.01.014

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] 炎症性遺伝子転写制御におけるヒストン脱メチル化の機能解析2019

    • Author(s)
      東島佳毅
    • Organizer
      第27回血管生物医学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ヒストン脱メチル化酵素Kdm7aはマウスにおいて前後軸形成を制御する2019

    • Author(s)
      東島佳毅、永井直、北沢太郎、河村悠美子、南学正臣、栗原裕基、和田洋一郎、古川哲史、神吉康晴
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ヒストン脱メチル化酵素Kdm7aはHox遺伝子群の転写制御を介して前後軸形成を制御する2019

    • Author(s)
      東島佳毅、永井直、北沢太郎、河村悠美子、南学正臣、栗原裕基、和田洋一郎、古川哲史、神吉康晴
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] クロマチン相互解析による血管炎症関連遺伝子の転写制御機構の解明2019

    • Author(s)
      東島佳毅
    • Organizer
      第1回ダウン症基礎研究会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Lysine demethylase 7a regulates anterior-posterior development via modulating Hox gene cluster transcription in mice2019

    • Author(s)
      Higashijima Y, Nagai N, Kitazawa T, Kawamura Y, Nagnaku M, Kurihara H, Wada Y, Kanki Y
    • Organizer
      Cell Symposia: Transcriptional Regulation in Evolution, Development, and Disease
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Lysine demthylase 7A and 6A dynamically modulate chromatin looping to control inflammatory gene transcription in human endothelial cells.2018

    • Author(s)
      Higashijima Y, Tsutsumi S, Link VM, Abe Y, Nangaku M, Wada Y, Glass CK, Furukawa T, Kanki Y.
    • Organizer
      EMBL Conference: Transcription and Chromatin.
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] miRNA-ヒストン修飾による動脈硬化関連遺伝子の転写制御機構解析2018

    • Author(s)
      東島佳毅、松井佑介、島村徹平、大坂瑞子、吉田雅幸、南学正臣、和田洋一郎、古川哲史、神吉康晴
    • Organizer
      第41回日本分子生物学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Transcriptional control of atherosclerosis-related genes through repressive histone marks and chromosomal interactions2018

    • Author(s)
      東島佳毅、堤修一、松井佑介、島村徹平、井上剛、南学正臣、和田洋一郎、古川哲史、神吉康晴
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] MicroRNA-3679-5p modulates the induction of adhesion molecules by targeting histone demethylases, KDM7A and UTX.2017

    • Author(s)
      Yoshiki HIGASHIJIMA, Tsuyoshi INOUE, Masaomi NANGAKU, Tatsuhiko KODAMA, Yasuharu KANKI, Youichiro WADA
    • Organizer
      第43回内藤コンファレンス
    • Related Report
      2017 Annual Research Report
  • [Presentation] 血管内皮細胞における炎症刺激に応じたmiRNA-ヒストン修飾ネットワーク機構2017

    • Author(s)
      東島 佳毅、神吉 康晴、井上 剛、南学 正臣、古川 哲史、和田 洋一郎
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Lysine Demethylase 6A And 7A Regulated By MicroRNA-3679-5p Mediates TNF-α-induced Inflammatory Signaling In Vascular Endothelium.2017

    • Author(s)
      Yoshiki HIGASHIJIMA,Tsuyoshi INOUE, Masaomi NANGAKU, Youichiro WADA, Tetsushi FURUKAWA,Yasuharu KANKI
    • Organizer
      American Heart Association 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research

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Published: 2017-05-25   Modified: 2024-03-26  

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