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Development of Imaging Method for HDAC Activity using DNA-binding Fluorescent Probe

Research Project

Project/Area Number 16K01933
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Chemical biology
Research InstitutionOsaka University

Principal Investigator

Minoshima Masafumi  大阪大学, 工学研究科, 助教 (20600844)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Keywords蛍光プローブ / HDAC / エピジェネティクス / DNA結合 / 蛍光イメージング / ヒストン脱アセチル化酵素 / エピゲノム創薬 / 化学プローブ / DNA
Outline of Final Research Achievements

In this study, we aim to develop fluorescence imaging of cellular histone deacetylase (HDAC) activity that involves in cancer and neurodegenerative diseases. The fluorescent probe increases DNA binding affinity and fluorescence intensity upon deacetylation of substrate. Modification of the probe structure by introduction of the substructure of HDAC inhibitor expanded the HDAC selectivity. We also improved turn-on ratio of the fluorescence signals by introducing multiple acetyllysine substrates. As a result, nuclear HDAC activity from HeLa cells was fluorescently detected using the modified fluorescent probe.

Academic Significance and Societal Importance of the Research Achievements

HDACはがんや神経変性疾患などの病態において高発現していることが知られており、薬剤の分子標的として注目されている。2006年にHDAC阻害剤が皮膚T細胞リンパ腫の治療薬として承認されて以降、数多くの阻害剤が開発され、研究が進められている。したがって、生細胞におけるHDACの活性を知ることは、その生理機能の理解だけでなく、薬剤開発においても非常に重要である。今回、細胞核内のHDAC活性を検出できたことで、環境変化における細胞内シグナルの変調を調べることや、疾患に対するHDAC阻害剤の細胞を用いた評価系に展開することが期待できる。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (28 results)

All 2019 2018 2017 2016

All Journal Article (11 results) (of which Peer Reviewed: 10 results,  Open Access: 4 results,  Acknowledgement Compliant: 1 results) Presentation (17 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results)

  • [Journal Article] In Vivo Multicolor Imaging with Fluorescent Probes Revealed the Dynamics and Function of Osteoclast Proton Pumps2019

    • Author(s)
      Minoshima Masafumi、Kikuta Junichi、Omori Yuta、Seno Shigeto、Suehara Riko、Maeda Hiroki、Matsuda Hideo、Ishii Masaru、Kikuchi Kazuya
    • Journal Title

      ACS Central Science

      Volume: 5 Issue: 6 Pages: 1059-1066

    • DOI

      10.1021/acscentsci.9b00220

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Photolytic Release of a Caged Inhibitor of an Endogenous Transcription Factor Enables Optochemical Control of CREB-Mediated Gene Expression2019

    • Author(s)
      Imoto Takuma、Kawase Akihiro、Minoshima Masafumi、Yokoyama Tatsushi、Bito Haruhiko、Kikuchi Kazuya
    • Journal Title

      Organic Letters

      Volume: 22 Issue: 1 Pages: 22-25

    • DOI

      10.1021/acs.orglett.9b03568

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of an effective protein-labeling system based on smart fluorogenic probes2019

    • Author(s)
      Reja SI, Minoshima M, Hori Y, Kikuchi K
    • Journal Title

      J Biol Inorg Chem

      Volume: 24 Issue: 4 Pages: 443-455

    • DOI

      10.1007/s00775-019-01669-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] In vivo Multicolor Imaging with Fluorescent Probes Revealed the Dynamics and Function of Osteoclast Proton Pumps2019

    • Author(s)
      Minoshima, Masafumi; Kikuta, Junichi; Omori, Yuta; Seno, Shigeto; Suehara, Riko; Maeda, Hiroki; Matsuda, Hideo; Ishii, Masaru; Kikuchi, Kazuya
    • Journal Title

      ACS Central Science

      Volume: in press

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Perfluorocarbon-based 19F MRI Nanoprobes for In Vivo Multicolor Imaging2018

    • Author(s)
      Akazawa, Kazuki; Sugihara, Fuminori; Nakamura, Tatsuya; Matsushita, Hisashi; Mukai, Hiroaki; Akimoto, Rena; Minoshima, Masafumi; Mizukami, Shin; Kikuchi, Kazuya
    • Journal Title

      Angew. Chem. Int. Ed

      Volume: 57 Pages: 16742-16747

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sensing caspase-1 activity using activatable 19F MRI nanoprobes with improved turn-on kinetics2018

    • Author(s)
      Akazawa Kazuki、Sugihara Fuminori、Minoshima Masafumi、Mizukami Shin、Kikuchi Kazuya
    • Journal Title

      Chemical Communications

      Volume: 54 Issue: 83 Pages: 11785-11788

    • DOI

      10.1039/c8cc05381b

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Dynamic Analyses of the Short-Term Effects of Different Bisphosphonates Using Intravital Two-Photon Microscopy2018

    • Author(s)
      Kikuta Junichi、Shirazaki Mai、Sudo Takao、Mizuno Hiroki、Morimoto Akito、Suehara Riko、Minoshima Masafumi、Kikuchi Kazuya、Ishii Masaru
    • Journal Title

      JBMR Plus

      Volume: 2 Issue: 6 Pages: 362-366

    • DOI

      10.1002/jbm4.10057

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] In vivo visualisation of different modes of action of biologic DMARDs inhibiting osteoclastic bone resorption2018

    • Author(s)
      Matsuura Y, Kikuta J, Kishi Y, Hasegawa T, Okuzaki D, Hirano T, Minoshima M, Kikuchi K, Kumanogoh A, Ishii M
    • Journal Title

      Annals of the Rheumatic Diseases

      Volume: 印刷中 Issue: 8 Pages: 1219-1225

    • DOI

      10.1136/annrheumdis-2017-212880

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Development of fluorescent probes for bone imaging in vivo ~Fluorescent probes for intravital imaging of osteoclast activity~2018

    • Author(s)
      Masafumi Minoshima, Kazuya Kikuchi
    • Journal Title

      Clinical Calcium

      Volume: 28 Pages: 187-191

    • Related Report
      2017 Research-status Report
  • [Journal Article] Intracellular Protein-Labeling Probes for Multicolor Single-Molecule Imaging of Immune Receptor?Adaptor Molecular Dynamics2017

    • Author(s)
      Sato Ryota、Kozuka Jun、Ueda Masahiro、Mishima Reiko、Kumagai Yutaro、Yoshimura Akimasa、Minoshima Masafumi、Mizukami Shin、Kikuchi Kazuya
    • Journal Title

      Journal of the American Chemical Society

      Volume: 139 Issue: 48 Pages: 17397-17404

    • DOI

      10.1021/jacs.7b08262

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Photostable and Photoswitching Fluorescent Dyes for Super-resolution Imaging2017

    • Author(s)
      M. Minoshima, K. Kikuchi
    • Journal Title

      Journal of Biological Inorganic Chemistry

      Volume: - Issue: 5 Pages: 1-14

    • DOI

      10.1007/s00775-016-1435-y

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] 機能性蛍光プローブを用いた骨溶解に関与する分子動態のin vivoイメージング2019

    • Author(s)
      蓑島 維文、大森 雄太、菊地 和也
    • Organizer
      第13回バイオ関連化学シンポジウム2019
    • Related Report
      2019 Annual Research Report
  • [Presentation] 破骨細胞プロトンポンプ動態・機能のin vivoイメージング解析2019

    • Author(s)
      蓑島 維文、大森 雄太、菊地 和也
    • Organizer
      日本ケミカルバイオロジー学会 第14回年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] β-ラクタマーゼ阻害剤を用いたタンパク質ラベル化蛍光プローブの開発2019

    • Author(s)
      梅野 太朗、Roux Margaux、蓑島 維文、菊地 和也
    • Organizer
      日本ケミカルバイオロジー学会 第14回年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Development of reversible protein labelling method using exchangeable fluorescent turn-on probes2019

    • Author(s)
      Reja Shahi Imam, Sowa Toshiyasu, Minoshima Masafumi, Kikuchi Kazuya
    • Organizer
      15th International Symposium on Applied Bioinorganic Chemistry
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] pH感受性蛍光プローブによる破骨細胞プロトンポンプ動態のin vivo観察2018

    • Author(s)
      蓑島維文、大森雄太、菊地和也
    • Organizer
      第27回バイオイメージング学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 発蛍光プローブを用いた可逆なタンパク質標識法の開発2018

    • Author(s)
      蓑島維文、岨 稔康、菊地和也
    • Organizer
      第12回バイオ関連化学合同シンポジウム
    • Related Report
      2018 Research-status Report
  • [Presentation] pH感受性赤色蛍光プローブによる破骨細胞プロトンポンプ動態の生体イメージング2018

    • Author(s)
      蓑島維文、大森雄太、菊地和也
    • Organizer
      第13回日本ケミカルバイオロジー学会
    • Related Report
      2018 Research-status Report
  • [Presentation] pH感受性赤色蛍光プローブを用いた破骨細胞プロトンポンプ動態のイメージング2018

    • Author(s)
      蓑島維文、大森雄太、菊田順一、石井 優、菊地和也
    • Organizer
      第13回分子イメージング学会総会・学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Intravital imaging of osteoclast V-ATPase function with pH-activatable red fluorescent probe2018

    • Author(s)
      Minoshima, Masafumi; Omori, Yuta; Kikuchi, Kazuya
    • Organizer
      World Molecular Imaging Congress (WMIC) 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] pH感受性赤色蛍光プローブによる破骨細胞V-ATPase動態の生体内リアルタイムイメージング2018

    • Author(s)
      大森雄太、前田拓樹、蓑島維文、菊地和也
    • Organizer
      日本化学会第98春季年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 生体内破骨細胞活性を検出するpH感受性赤色蛍光プローブの開発2017

    • Author(s)
      大森雄太、前田拓樹、蓑島維文、菊地和也
    • Organizer
      日本化学会第97春季年会
    • Place of Presentation
      慶應義塾大学(神奈川県・横浜市)
    • Year and Date
      2017-03-16
    • Related Report
      2016 Research-status Report
  • [Presentation] 蛋白質ラベル化プローブを用いた細胞内タンパク質の多色1分子イメージング2017

    • Author(s)
      蓑島維文、佐藤亮太、小塚 淳、熊谷雄太郎、水上 進、菊地和也
    • Organizer
      日本ケミカルバイオロジー学会 第12回年会
    • Related Report
      2017 Research-status Report
  • [Presentation] クロマチン修飾酵素の活性を検出する化学プローブ2017

    • Author(s)
      蓑島維文
    • Organizer
      第九回「光塾」
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] pH感受性赤色蛍光プローブを用いた生体内破骨細胞活性リアルタイムイメージング2017

    • Author(s)
      蓑島維文、大森雄太、前田拓樹、菊田順一、石井 優、菊地和也
    • Organizer
      日本分子イメージング学会 第12回総会・学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 蛍光プローブとDNAを用いたHDAC活性検出法の開発2016

    • Author(s)
      立松結花、蓑島維文、菊地和也
    • Organizer
      第25回日本バイオイメージング学会学術集会
    • Place of Presentation
      名古屋市立大学(愛知県・名古屋市)
    • Year and Date
      2016-09-05
    • Related Report
      2016 Research-status Report
  • [Presentation] Development of DNA-binding fluorescent probe for detection of histone deacetylase activity2016

    • Author(s)
      Masafumi Minoshima, Yuka Tatematsu, Tetsuaki Matsumoto, Kazuya Kikuchi
    • Organizer
      EMBO Conference 2016: Chemical Biology
    • Place of Presentation
      Heiderberg, Germany
    • Year and Date
      2016-08-31
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] DNA結合性蛍光プローブによるHDAC活性検出手法の開発2016

    • Author(s)
      蓑島維文、立松結花、松本哲明、菊地和也
    • Organizer
      日本ケミカルバイオロジー学会第11回年会
    • Place of Presentation
      京都テルサ(京都府・京都市)
    • Year and Date
      2016-06-15
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2021-02-19  

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