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Development of electrophysiological indices to predict proarrhythmic risk of a drug in a human iPS cell-derived cardiomyocytes' sheet through its functional characterization

Research Project

Project/Area Number 17K08608
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General pharmacology
Research InstitutionToho University

Principal Investigator

Izumi-Nakaseko Hiroko  東邦大学, 医学部, 准教授 (80408773)

Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsヒトiPS細胞由来心筋細胞 / 多電極システム / 催不整脈性 / 抗不整脈性 / イオンチャネル / モーションベクトル / 心毒性 / 電気生理学 / 電気薬理学 / ヒトiPS細胞 / 心筋細胞 / マルチチャネル遮断薬 / トキシコロジー / QT延長症候群 / iPS
Outline of Final Research Achievements

In this project, I developed electrophysiological indices for human iPS cell-derived cardiomyocytes’ monolayer sheets to outline the pro- and/or anti-arrhythmic properties of drugs. Each cell sheet was prepared on each microelectrode-array probe, and then paced with programmed stimuli via a pair of adjacent electrodes before and after drug treatment. I examined the electrophysiological indices of the cell sheet for detecting Na+ channel blockade with its characteristics, blockade of K+ and Ca2+ channels, and their balance in the repolarization phase using clinical antiarrhythmics. I then assessed an anticancer agent and a Kampo preparation with the indices and detected their multichannel blocking actions. The obtained results indicated that the cell sheets with the indices could be valuable to predict pro- and/or anti-arrhythmic action of a substance in the human intact heart.

Academic Significance and Societal Importance of the Research Achievements

多くの薬物が主作用の他に、心臓のイオンチャネルを修飾し、その結果、催不整脈性や抗不整脈性を持つことが明らかになっており、その作用を見極めることは大変重要である。ヒトiPS心筋細胞はヒトの生体心と同じイオンチャネルを発現しているので、この細胞を使用して催不整脈性や抗不整脈性を正確に評価できれば、種差もなく、ヒト生体心へその結果を外挿することが出来る。本研究では2 mm四方のヒトiPS細胞由来心筋細胞シートに多電極システムと電気刺激を組み合わせることにより、複数のイオンチャネル遮断作用をもつ薬物であっても催不整脈性や抗不整脈性の概要が把握できる電気生理学的指標を開発した。

Report

(5 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (26 results)

All 2021 2020 2019 2018 2017

All Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (20 results) (of which Int'l Joint Research: 5 results,  Invited: 1 results)

  • [Journal Article] Optimizing the Direction and Order of the Motion Unveiled the Ability of Conventional Monolayers of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Show Frequency-Dependent Enhancement of Contraction and Relaxation Motion2020

    • Author(s)
      Izumi-Nakaseko Hiroko、Chiba Koki、Hagiwara-Nagasawa Mihoko、Satsuka Ayano、Goto Ai、Nunoi Yoshio、Kambayashi Ryuichi、Matsumoto Akio、Takei Yoshinori、Kanda Yasunari、Naito Atsuhiko T.、Sugiyama Atsushi
    • Journal Title

      Frontiers in Cell and Developmental Biology

      Volume: 8 Pages: 542562-542562

    • DOI

      10.3389/fcell.2020.542562

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dasatinib can Impair Left Ventricular Mechanical Function But May Lack Proarrhythmic Effect: A Proposal of Non-clinical Guidance for Predicting Clinical Cardiovascular Adverse Events of Tyrosine Kinase Inhibitors.2020

    • Author(s)
      Izumi-Nakaseko H, Fujiyoshi M, Hagiwara-Nagasawa M, Goto A, Chiba K, Kambayashi R, Naito AT, Ando K, Kanda Y, Ishii I, Sugiyama A
    • Journal Title

      Cardiovasc Toxicol.

      Volume: 20(1) Issue: 1 Pages: 58-70

    • DOI

      10.1007/s12012-019-09538-5

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Analysis of electro-mechanical relationship in human iPS cell-derived cardiomyocytes sheets under proarrhythmic condition assessed by simultaneous field potential and motion vector recordings.2019

    • Author(s)
      Sugiyama A, Hagiwara-Nagasawa M, Kambayashi R, Goto A, Chiba K, Naito AT, Kanda Y, Matsumoto A, Izumi-Nakaseko H
    • Journal Title

      J Pharmacol Sci

      Volume: 140(4) Issue: 4 Pages: 317-320

    • DOI

      10.1016/j.jphs.2019.07.006

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Assessment of the drug-induced toxicity on left ventricular function by pattern-cultured hiPSC-CMs.2019

    • Author(s)
      Naito A, Ito M, Gao F, Furuya A, Izumi-Nakaseko H, Hagiwara-Nagasawa M, Sugiyama A
    • Journal Title

      J Pharmacol Toxicol Methods

      Volume: 99 Pages: 106595-106595

    • DOI

      10.1016/j.vascn.2019.05.171

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Application of human induced pluripotent stem cell-derived cardiomyocytes sheets with microelectrode array system to estimate antiarrhythmic properties of multi-ion channel blockers2018

    • Author(s)
      Izumi-Nakaseko Hiroko、Hagiwara-Nagasawa Mihoko、Naito Atsuhiko T.、Goto Ai、Chiba Koki、Sekino Yuko、Kanda Yasunari、Sugiyama Atsushi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 137 Issue: 4 Pages: 372-378

    • DOI

      10.1016/j.jphs.2018.07.011

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of correction formula for field potential duration of human induced pluripotent stem cell-derived cardiomyocytes sheets2017

    • Author(s)
      Izumi-Nakaseko H, Kanda Y, Nakamura Y, Hagiwara-Nagasawa M, Wada T, Ando K, Naito AT, Sekino Y, Sugiyama A
    • Journal Title

      Journal of pharmacological sciences

      Volume: 135 Issue: 1 Pages: 44-50

    • DOI

      10.1016/j.jphs.2017.08.008

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 生薬甘草の心臓への電気薬理学的作用: in vitroとin vivoモデルを用いた統合的解析2021

    • Author(s)
      中瀬古(泉)寛子, 千葉浩輝, 後藤愛, 神林隆一, 布井啓雄, 長澤(萩原)美帆子, 松本明郎, 武井義則, 川合眞一, 杉山篤
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Effects of hyperglycemia and hyperosmolarity on cardiac electrophysiology and hemodynamics in in vivo canine model2021

    • Author(s)
      Izumi-Nakaseko H, Goto A, Kambayashi R, Hirokawa Y, Hagiwara-Nagasawa M, Nunoi Y, Takei Y, Matsumoto A, Kawai S, Taubel J, Sugiyama A
    • Organizer
      第98回日本生理学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Development and assessment of a new in vitro platform of human induced pluripotent stem cell-derived cardiomyocytes for evaluating the drug-induced biological phenomena predicting clinically observed cardiac effects.2020

    • Author(s)
      Izumi-Nakaseko H, Chiba K, Hagiwara-Nagasawa M, Goto A, Nunoi Y, Kambayashi R, Matsumoto A, Kanda Y, Naito AT, Sugiyama A
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Physiological properties of excitation-contraction relationships in human induced pluripotent stem cell-derived cardiomyocytes sheets.2020

    • Author(s)
      Izumi-Nakaseko H, Chiba K, Hagiwara-Nagasawa M, Goto A, Nunoi Y, Kambayashi R, Matsumoto A, Kanda Y, Naito AT, Sugiyama A
    • Organizer
      第97回日本生理学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] チロシンキナーゼ阻害薬のヒト心血管有害作用を予測する非臨床的評価方法の開発2019

    • Author(s)
      中瀬古(泉)寛子, 藤吉正哉, 長澤(萩原)美帆子, 安東賢太郎, 内藤篤彦, 石井伊都子, 杉山篤
    • Organizer
      第4回J-ISCP年次学術集会(国際心血管薬物療法学会日本部会)
    • Related Report
      2019 Research-status Report
  • [Presentation] 抗がん薬の心血管有害作用検出のための非臨床的評価プロトコルの提案2019

    • Author(s)
      中瀬古(泉)寛子, 杉山篤
    • Organizer
      第2回日本腫瘍循環器学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] ダサチニブは左心機能を低下するが、催不整脈作用を示さない:チロシンキナーゼ阻害薬のヒト心血管有害作用を予測する非臨床的評価方法の開発2019

    • Author(s)
      中瀬古(泉)寛子, 藤吉正哉, 長澤(萩原)美帆子, 後藤愛, 千葉浩輝, 神林隆一, 内藤篤彦, 安東賢太郎, 諫田泰成, 石井伊都子, 杉山篤
    • Organizer
      第141回日本薬理学会関東部会
    • Related Report
      2019 Research-status Report
  • [Presentation] Electrophysiological analyses of multi-ion channel blockers in hiPSC-CMs sheets with MEA system2019

    • Author(s)
      Izumi-Nakaseko H, Naito AT, Sekino Y, Hagiwara-Nagasawa M, Goto A, Chiba K, Kanda Y, Sugiyama A
    • Organizer
      9th FAOPS Congress(Kobe, Japan)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ダサチニブは左室機能を抑制する一方、催不整脈性はない:in vivoとin vitro実験系の併用研究2019

    • Author(s)
      中瀬古(泉)寛子, 石井伊都子, 藤吉正哉, 長澤(萩原)美帆子, 安東賢太郎, 内藤篤彦, 杉山篤
    • Organizer
      第10回日本安全性薬理研究会(東京, 日本)
    • Related Report
      2018 Research-status Report
  • [Presentation] ヒトiPS由来心筋細胞と多電極システムを用いた多チャネル遮断薬の電気薬理学的作用の検出2019

    • Author(s)
      中瀬古(泉)寛子, 長澤(萩原)美帆子, 内藤篤彦, 後藤愛, 千葉浩輝, 関野祐子, 諫田泰成, 杉山篤
    • Organizer
      第92回日本薬理学会年会(大阪, 日本)
    • Related Report
      2018 Research-status Report
  • [Presentation] Assessment of the drug-induced cardiac functional toxicity by pattern-cultured hiPSC-CMs.2018

    • Author(s)
      Naito AT, Ito M, Izumi-Nakaseko H, Ando K, Hagiwara-Nagasawa M, Nakamura Y, Sugiyama A
    • Organizer
      WCP2018(Kyoto)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Development of correction formula for frequency-dependent changes of field potential duration of human induced pluripotent stem cell-derived cardiomyocytes sheets.2018

    • Author(s)
      Izumi-Nakaseko H, Kanda Y, Nakamura Y, Hagiwara-Nagasawa M, Ando K, Naito AT, Sekino Y, Sugiyama A
    • Organizer
      WCP2018(Kyoto)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] モンゴル薬用植物Adonis mongolicaの心血管系に対する薬理作用2018

    • Author(s)
      中瀬古(泉)寛子, 李巍, 長澤(萩原)美帆子, 田中耕一郎 , Choijamts G, Batkhuyag P, Yeruult C, Khaliun N, Narantungalag D, 内藤篤彦, 小池一男, 杉山篤
    • Organizer
      第20回応用薬理シンポジウム(東京)
    • Related Report
      2018 Research-status Report
  • [Presentation] ヒト人工多能性幹細胞由来心筋細胞シートの細胞外電位持続時間の補正式の開発2018

    • Author(s)
      中瀬古(泉)寛子, 諫田泰成, 長澤(萩原)美帆子, 内藤篤彦, 関野祐子, 杉山篤
    • Organizer
      第20回応用薬理シンポジウム(東京)
    • Related Report
      2018 Research-status Report
  • [Presentation] Assessment of the drug-induced toxicity against left ventricular function by pattern-cultured hiPSC-CMs.2018

    • Author(s)
      Naito AT, Ito M, Gao FY, Furuya A, Izumi-Nakaseko H, Mihoko Hagiwara-Nagasawa M, Sugiyama A
    • Organizer
      Safety Pharmacology Science Annual Meeting(Washington DC, USA)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] がん分子標的薬dasatinibの心毒性の定量評価2018

    • Author(s)
      中瀬古(泉)寛子, 石井伊都子, 藤吉正哉, 長澤(萩原)美帆子, 安東賢太郎, 内藤篤彦, 杉山 篤
    • Organizer
      ダイバーシティ研究環境実現イニシアティブ 共同研究推進のためのセミナー&研究発表会(千葉)
    • Related Report
      2018 Research-status Report
  • [Presentation] ヒトiPS細胞由来心筋細胞シートを用いたマルチチャネル遮断薬の抗不整脈作用の評価2018

    • Author(s)
      中瀬古(泉)寛子, 長澤(萩原)美帆子, 内藤篤彦, 後藤愛, 千葉浩輝, 関野祐子, 諫田泰成, 杉山篤
    • Organizer
      第28回日本循環薬理学会(東京)
    • Related Report
      2018 Research-status Report
  • [Presentation] Electrophysiological characterization of the field potential duration in human induced pluripotent stem cell-derived cardiomyocytes sheets2018

    • Author(s)
      Izumi-Nakaseko H, Kanda Y, Nakamura Y, Hagiwara-Nagasawa M, Wada T, Ando K, Naito AT, Sekino Y, Sugiyama A
    • Organizer
      第95回日本生理学会大会
    • Related Report
      2017 Research-status Report
  • [Presentation] Characterization of frequent-dependent changes of field potential duration in human induced pluripotent stem cell-derived cardiomyocytes sheets2017

    • Author(s)
      Izumi-Nakaseko H, Kanda Y, Nakamura Y, Hagiwara-Nagasawa M, Wada T, Ando K, Naito AT, Sekino Y, Sugiyama A
    • Organizer
      第27回日本循環薬理学会
    • Related Report
      2017 Research-status Report
  • [Presentation] Development of correction formula for field potential duration of human induced pluripotent stem cell-derived cardiomyocytes sheets.2017

    • Author(s)
      Izumi-Nakaseko H, Kanda Y, Nakamura Y, Hagiwara-Nagasawa M, Wada T, Ando K, Naito AT, Sekino Y, Sugiyama A
    • Organizer
      第64回日本不整脈心電学会学術大会
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2022-01-27  

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