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Research on pathogenesis and development of therapies for cardiac failure using dystrophin-deficient-cardiomyocytes derived from DMD patients

Research Project

Project/Area Number 18K07064
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49030:Experimental pathology-related
Research InstitutionShinshu University

Principal Investigator

Miyazaki Daigo  信州大学, 医学部附属病院, 講師(特定雇用) (80596370)

Co-Investigator(Kenkyū-buntansha) 中村 昭則  信州大学, 医学部, 特任教授 (10303471)
柴 直子  信州大学, 医学部, 助教 (00639289)
柴 祐司  信州大学, 学術研究院医学系, 教授 (70613503)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsDuchenne型筋ジストロフィー / 心不全 / IGF2 / デュシェンヌ型筋ジストロフィー / 心筋細胞 / iPS細胞 / ジストロフィン
Outline of Final Research Achievements

Heart failure is now becoming the most frequent cause of death in Duchenne muscular dystrophy (DMD); however, the pathomechanisms of cardiomyopathy remain unclear. We generated cardiomyocytes from DMD-specific induced pluripotent stem cells (DMD-iPSC-CMs) donated from a DMD patient, and microarray analysis revealed several proliferation-, regeneration- related genes were down-regulated in DMD-iPSC-CMs. In these genes, IGF2 and TMSB4X gene expressions were recovered along with dystrophin restoration by exon skipping in DMD-iPSC-CMs. Next, we treated iPSC-CMs from healthy person with IGF2 and TMSB4X specific siRNAs. IGF2 knock-down tend to lead decreased size of cardiomyocytes, and led to significant down-regulation of IGF1 in these iPSC-CMs. IGF1 and IGF2 bind IGF1R and activate Erk signal transduction, and are thought to maintain the size of cardiomyocyte and myocardial wall thickness. IGF2 down-regulation might deteriorate the pathology of dilated cardiomyopathy in DMD.

Academic Significance and Societal Importance of the Research Achievements

心不全はDMDの主な死亡原因となる重要な障害であるが,心不全に関する研究は心筋の採取が難しく十分に進んでいない.DMD患者由来の心筋細胞の作成と網羅的遺伝子解析の結果, さらに健常者由来の心筋細胞に対するsiRNAによる遺伝子発現抑制実験の結果から,DMD患者由来の心筋細胞におけるIGF2発現の低下は、DMD患者の拡張型心筋症の病態を悪化させる可能性が示唆され,学術的意義のみならず心不全治療開発の基礎として社会的意義のある成果と考える.

Report

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

    (7 results)

All 2021 2020 2019 2018

All Presentation (7 results)

  • [Presentation] TMSB4X and IGF2 down-regulation in dystrophin-deficient cardiomyocyte derived from DMD2021

    • Author(s)
      Daigo Miyazaki
    • Organizer
      第62回日本神経学会学術大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Decrease of differentiation- and regeneration-related genes in dystrophin-deficient cardiomyocytes2020

    • Author(s)
      Daigo Miyazaki
    • Organizer
      第61回日本神経学会学術大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Gene expression in cardiomyocytes from DMD with exon 46-55 deletion after exon 45 skipping therapy2019

    • Author(s)
      Daigo Miyazaki
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Research-status Report 2018 Research-status Report
  • [Presentation] DMD患者由来心筋細胞における分化・再生関連遺伝子の発現低下と心筋障害への影響に関する研究2019

    • Author(s)
      宮崎 大吾
    • Organizer
      第14回筋ジストロフィー治療研究合同発表会
    • Related Report
      2019 Research-status Report
  • [Presentation] Decrease of genes associated with differentiation and regeneration in cardiomyocyte derived from DMD2018

    • Author(s)
      Daigo Miyazaki
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Research-status Report
  • [Presentation] DMD患者iPS細胞由来の心筋細胞における分化・再生関連遺伝子の発現低下と心筋障害の発症機序に関する研究/Decrease of differentiation- and regeneration-associated genes in dystrophin-deficit cardiomyocyte derived from DMD2018

    • Author(s)
      宮崎大吾
    • Organizer
      日本筋学会第4回学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] DMD患者iPS細胞由来の心筋細胞における分化・再生関連遺伝子の発現低下とエクソン・スキップ治療後の変化に関する研究2018

    • Author(s)
      宮崎 大吾
    • Organizer
      第13回筋ジストロフィー治療研究合同発表会
    • Related Report
      2018 Research-status Report

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

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