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Intracellular signal transduction regulating necroptosis of cardiomyocytes

Research Project

Project/Area Number 21K08035
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionSapporo Medical University

Principal Investigator

Miura Tetsuji  札幌医科大学, 医学部, 名誉教授 (90199951)

Co-Investigator(Kenkyū-buntansha) 丹野 雅也  札幌医科大学, 医学部, 准教授 (00398322)
矢野 俊之  札幌医科大学, 医学部, 講師 (40444913)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2023: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000)
Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2021: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywords心不全 / 細胞死 / ネクロプトーシス / 細胞内シグナル伝達 / 細胞内情報伝達 / 細胞骨格
Outline of Research at the Start

これまでの我々のネクロプトーシスに関する研究成果を踏まえて、本研究では心筋細胞のネクロプトーシスを制御するシグナルを、リン酸化MLKL(mixed lineage kinase domain-like)の細胞内移行と介在板構成蛋白との関連に焦点を当てて解明することを目的とする。検証を目指す仮説は、「心筋細胞のネクロプトーシスの機序において、介在板を構成する細胞内骨格蛋白がネクロプトーシス・シグナルの制御に関与しており、介在板領域での細胞膜破綻が慢性心不全における心筋細胞の脱落と心室拡大に寄与している」というものである。この仮説を培養心筋細胞とマウスの慢性心不全モデルを用いて検証する。

Outline of Final Research Achievements

This study showed that phosphorylated MLKL (p-MLKL) translocated to nuclei by activation of necroptotic signals mediate cell death via a RIP1/RIP3-independent mechanism, while disruption of the cell membrane by p-MLKL translocated to the membrane occurs a RIP1 and/or RIP3-dependent mechanisms. In chronic heart failure, p-MLKL was found to additionally translocate to intercalated discs, where it may play a role in conduction and contraction abnormalities.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、核に移行したリン酸化MLKLを介した新たなネクロプロートシスの機序が明らかにされ、慢性心不全の病態で特徴的に加わる介在板リン酸化MLKL発現亢進の障害性も示された。さらにそうしたMLKLを介した心筋障害の抑制にはRIP1/RIP3の阻害では不十分であり、MLKLを直接標的とした治療が必要であることが示唆された。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (8 results)

All 2024 2023 2022 2021

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 5 results) Presentation (1 results)

  • [Journal Article] Role of AMP deaminase in diabetic cardiomyopathy2024

    • Author(s)
      Miura T, Kouzu H, Tanno M, Tatekoshi Y, Kuno A
    • Journal Title

      Molecular and Cellular Biochemistry

      Volume: - Issue: 12 Pages: 3195-3211

    • DOI

      10.1007/s11010-024-04951-z

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adenosine monophosphate deaminase in the endoplasmic reticulummitochondria interface promotes mitochondrial Ca2+ overload in type 2 diabetes rat hearts.2023

    • Author(s)
      Osanami A, Sato T, Toda Y, Shimizu M, Kuno A, Kouzu H, Yano T, Ohwada W, Ogawa T, Miura T, Tanno M.
    • Journal Title

      J Diabetes Investig

      Volume: 14 Issue: 4 Pages: 560-569

    • DOI

      10.1111/jdi.13982

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nuclear translocation of MLKL enhances necroptosis by a RIP1/RIP3-independent mechanism in H9c2 cardiomyoblasts.2023

    • Author(s)
      Ino S, Yano T, Kuno A, Tanno M, Kouzu H, Sato T, Yamashita T, Ohwada W, Osanami A, Ogawa T, Toda Y, Shimizu M, Miura T.
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 151 Issue: 2 Pages: 134-143

    • DOI

      10.1016/j.jphs.2022.12.009

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy2022

    • Author(s)
      Fujita Y, Yano T, Kanamori H, Nagahara D, Muranaka A, Kouzu H, Mochizuki A, Koyama M, Nagano N, Fujito T, Nishikawa R, Kamiyama N, Tanaka M, Kuno A, Tanno M, Miura T
    • Journal Title

      ESC Heart Failure

      Volume: 9 Issue: 5 Pages: 3435-3451

    • DOI

      10.1002/ehf2.14059

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diabetes modulation of the myocardial infarction-acute kidney injury axis2022

    • Author(s)
      Miura Tetsuji、Kuno Atsushi、Tanaka Marenao
    • Journal Title

      American Journal of Physiology-Heart and Circulatory Physiology

      Volume: 322 Issue: 3 Pages: H394-H405

    • DOI

      10.1152/ajpheart.00639.2021

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of Erythropoiesis-Stimulating Agents in Cardiovascular Protection in CKD Patients: Reappraisal of Their Impact and Mechanisms2022

    • Author(s)
      Miura Tetsuji、Sato Tatsuya、Yano Toshiyuki、Takaguri Akira、Miki Takayuki、Tohse Noritsugu、Nishizawa Keitaro
    • Journal Title

      Cardiovascular Drugs and Therapy

      Volume: Online ahead of print. Issue: 6 Pages: 00-00

    • DOI

      10.1007/s10557-022-07321-3

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Involvement of necroptosis in contrast-induced nephropathy in a rat CKD model2021

    • Author(s)
      Shibata Satoru、Moniwa Norihito、Kuno Atsushi、Kimura Ayumu、Ohwada Wataru、Sugawara Hirohito、Gocho Yufu、Tanaka Marenao、Yano Toshiyuki、Furuhashi Masato、Tanno Masaya、Miki Takayuki、Miura Tetsuji
    • Journal Title

      Clinical and Experimental Nephrology

      Volume: Online ahead of print Issue: 7 Pages: 708-717

    • DOI

      10.1007/s10157-021-02048-1

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Enhanced nuclear localization of MLKL promotes necroptosis of cardiomyocytes and predicts prognosis in dilated cardiomyopathy.2023

    • Author(s)
      YanoT, Fujita Y, Ino S, Ohwada W, Kouzu H, Kuno A, Tanno M, Furuhashi M, Miura T.
    • Organizer
      第87回日本循環器学会学術集会
    • Related Report
      2022 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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