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Elucidation of the pathogenic mechanism of HCM using isogenic hiPSC-CMs with HCM mutation

Research Project

Project/Area Number 18K15120
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 49030:Experimental pathology-related
Research InstitutionKyoto University

Principal Investigator

Miki Kenji  京都大学, iPS細胞研究所, 研究員 (10772759)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
KeywordsHCM / isogenic hiPSC / ゲノム編集 / isogenic / iPS / MYH7-R719Q / RNA-seq / hiPS細胞 / isogenic iPS細胞 / CRISPR
Outline of Final Research Achievements

In this study, I established several hiPSC lines with isogenic HCM mutations using CRISPR/Cas9 technology, and differentiated them into cardiomyocytes (CMs). I found that CMs with MYH7-R719Q mutation showed significant cardiac hypertrophy at the cellular level. Next, I performed the screening of compounds that inhibit hypertrophy in this hiPSC-CMs and identified the target gene by chemical proteomics using the compound (Gene name is unpublished as of this moment). In addition, the hiPSCs in which the gene was knocked out showed cardiac hypertrophy at the cellular level similar to that of human iPS cells with the MYH7-R719Q mutation. Although further analysis is needed, I have found a possible new mechanism of cardiac hypertrophy that has not been reported before.
Furthermore, I was able to publish two papers related to this research within a period of time.

Academic Significance and Societal Importance of the Research Achievements

HCMの原因遺伝子としてこれまで10種以上の遺伝子及び900以上の突然変異が報告されており、様々なHCM患者由来のiPS細胞を用いて研究されているが、そのメカニズムの解明及び有効な治療薬の開発には至っていない。私はisogenic変異株を用いる戦略で同一の遺伝的背景を持つ複数のHCM変異iPS細胞株を作製し、これらを詳細に解析することで、これまで報告されていない新規のHCMメカニズムの可能性を見出した。このメカニズムをさらに解析することで、多くのHCM患者に適応できる治療薬の開発に繋がる可能性があるとともに、今回採用した戦略は様々な疾患領域へ応用可能な方法であり、その意義は大きいと考えている。

Report

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

    (6 results)

All 2021 2020 2019 2018

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (4 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] ERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes2021

    • Author(s)
      Kenji Miki, Kohei Deguchi, Misato Nakanishi-Koakutsu et al.
    • Journal Title

      Nature Communications

      Volume: in press

    • NAID

      120007089250

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Human iPS-derived Pre-epicardial Cells Direct Cardiomyocyte Aggregation, Expansion and Organization In Vitro2021

    • Author(s)
      Jun Jie Tan, Jacques Paul Guyette, Kenji Miki et al.
    • Journal Title

      Nature Communications

      Volume: in press

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Differential expression levels of CD151 enable enrichment of atrial cardiomyocytes derived from human induced-pluripotent stem cell2020

    • Author(s)
      Misato Koakutsu, Kenji Miki, Yuki Naka, Masako Sasaki, Stephanie C Napier, Tomoyuki Nishimoto and Yoshinori Yoshida
    • Organizer
      European Society of Cardiology Congress
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Promising small molecules ameliorated morphological abnormalities of hypertrophic cardiomyopathy in iPS cell-derived cardiomyocytes.2019

    • Author(s)
      Kohei Deguchi, Kenji Miki, Shigeru Kondo, Ayaka Sakoda, Tsukasa Sugo, Kenichi Imahashi, Tomoyuki Nishimoto, and Yoshinori Yoshida
    • Organizer
      American Heart Association Scientific Sessions 2019
    • Related Report
      2019 Research-status Report
  • [Presentation] Identification of a Cell Surface Marker which is Differentially Expressed between Ventricular and Atrial Cardiomyocytes Derived from Human Induced-pluripotent Stem Cell2019

    • Author(s)
      Misato Koakutsu, Kenji Miki, Masako Sasaki, Stephanie Napier, Tomoyuki Nishimoto, and Yoshinori Yoshida
    • Organizer
      American Heart Association Scientific Sessions 2019
    • Related Report
      2019 Research-status Report
  • [Presentation] ゲノム編集によって作製した疾患iPS心筋細胞を用いた肥大型心筋症治療薬の開発2018

    • Author(s)
      出口康平、三木健嗣、近藤滋、周郷司、西本誠之、吉田善紀
    • Organizer
      第4回心筋症研究会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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