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Elucidation of novel molecular mechanisms of the treatment strategy for heart failure by inactivating the DNA damage response

Research Project

Project/Area Number 19K08560
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

Miyata Keishi  熊本大学, 大学院生命科学研究部(医), 客員教授 (50398228)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords心不全 / DNA損傷応答
Outline of Research at the Start

近年心不全を発症した心筋細胞では断片化DNAの蓄積だけでなくDNA 損傷応答(DDR)活性化を認めており、DDR に誘導される炎症性サイトカイン活性が心不全悪化を促進しており、心不全病態形成においてDDR 活性化が重要な役割を果たしていることが明らかとなっている。しかし心不全病態形成においてDDR 活性化を制御する詳細な分子機構は十分に解明されていない。本研究ではDDR 制御関連遺伝子改変マウスを用いてモデルマウス作製し心不全病態形成におけるDDR 活性制御の詳細な分子機構の解明を行い、DDR 不活性化による心不全病態の進展を遅延あるいは阻止する新たな治療戦略の開発に繋がる研究基盤を確立する。

Outline of Final Research Achievements

Recently, cardiomyocytes that have developed heart failure show not only accumulation of fragmented DNA but also DNA damage response (DDR) activation is observed, and inflammatory cytokines induced by DDR exacerbate the development of heart failure. Although it has been clarified that DDR activation of cardiomyocytes plays an important role in the development of heart failure pathology, the detailed molecular mechanism that regulates DDR activation in cardiomyocytes is not fully elucidated. In this study, the analysis of heart failure model mice using DDR-related gene-modified mice revealed that reducing the expression of Hint1 in cardiomyocytes suppresses DDR activation in the development of heart failure and has a cardioprotective effect. Furthermore, reducing Hint1 expression was found to suppress the cardiotoxicity of adriamycin caused by DDR.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、依然として予後不良の疾患である心不全に対してDDR活性化抑制という新たな観点からの予防や新規治療法開発に繋がる可能性が期待される。さらに、近年、高齢化によって循環器疾患とがんを合併する患者が多く認められ、化学療法の進歩によりがんの治療率は格段に向上しているが、それに伴って薬剤による心毒性という副作用が問題となっている。本研究の成果はDDR活性化が原因とされるアドリアマイシンの心毒性の軽減にも繋がる可能性がある。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (15 results)

All 2021 2020 2019 Other

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

  • [Int'l Joint Research] University of Utah(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] ユタ大学(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] ユタ大学(米国)

    • Related Report
      2019 Research-status Report
  • [Journal Article] Hyperglycemia and Thrombocytopenia ― Combinatorially Increase the Risk of Mortality in Patients With Acute Myocardial Infarction Undergoing Veno-Arterial Extracorporeal Membrane Oxygenation ―2021

    • Author(s)
      Okadome Yusuke、Morinaga Jun、Fukami Hirotaka、Hori Kota、Ito Teruhiko、Sato Michio、Miyata Keishi、Kuwabara Takashige、Mukoyama Masashi、Suzuki Ryusuke、Tsunoda Ryusuke、Oike Yuichi
    • Journal Title

      Circulation Reports

      Volume: 3 Issue: 12 Pages: 707-715

    • DOI

      10.1253/circrep.CR-21-0043

    • NAID

      130008128243

    • ISSN
      2434-0790
    • Year and Date
      2021-12-10
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The lncRNA Caren antagonizes heart failure by inactivating DNA damage response and activating mitochondrial biogenesis2021

    • Author(s)
      Sato Michio, Kadomatsu Tsuyoshi, Miyata Keishi, Warren Junco S., Tian Zhe、Node Koichi、Araki Kimi、 Oike Yuichi et al
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 2529-2529

    • DOI

      10.1038/s41467-021-22735-7

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia2021

    • Author(s)
      Fukami Hirotaka、Morinaga Jun、Nakagami Hironori、Hayashi Hiroki、Okadome Yusuke、Matsunaga Eiji、Kadomatsu Tsuyoshi、Horiguchi Haruki、Sato Michio、Sugizaki Taichi、Kuwabara Takashige、Miyata Keishi、Mukoyama Masashi、Morishita Ryuichi、Oike Yuichi
    • Journal Title

      Cell Reports Medicine

      Volume: 2 Issue: 11 Pages: 100446-100446

    • DOI

      10.1016/j.xcrm.2021.100446

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Circulating angiopoietin-like protein 2 levels and arterial stiffness in patients receiving maintenance hemodialysis: A cross-sectional study.2020

    • Author(s)
      Fukami H, Morinaga J, Okadome Y, Nishiguchi Y, Iwata Y, Kanki T, Nakagawa T, Izumi Y, Kakizoe Y, Kuwabara T, Horiguchi H, Sato M, Kadomatsu T, Miyata K, Tajiri T, Oike Y, Mukoyama M.
    • Journal Title

      Atherosclerosis.

      Volume: 315 Pages: 18-23

    • DOI

      10.1016/j.atherosclerosis.2020.10.890

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Febuxostat, a Xanthine Oxidase Inhibitor, Decreased Macrophage Matrix Metalloproteinase Expression in Hypoxia.2020

    • Author(s)
      Wei S, Isagawa T, Eguchi M, Sato D, Tsukano H, Miyata K, Oike Y, Takeda N, Ikeda S, Kawano H, Maemura K.
    • Journal Title

      Biomedicines.

      Volume: 8(11) Issue: 11 Pages: 470-470

    • DOI

      10.3390/biomedicines8110470

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stroma-derived ANGPTL2 establishes an anti-tumor microenvironment during intestinal tumorigenesis2020

    • Author(s)
      Horiguchi Haruki、Kadomatsu Tsuyoshi、Miyata Keishi、Terada Kazutoyo、Sato Michio、Torigoe Daisuke、Morinaga Jun、Moroishi Toshiro、Oike Yuichi
    • Journal Title

      Oncogene

      Volume: 40 Issue: 1 Pages: 55-67

    • DOI

      10.1038/s41388-020-01505-7

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Melinjo seed extract increases adiponectin multimerization in physiological and pathological conditions.2020

    • Author(s)
      K. Oniki, T. Kawakami, A. Nakashima, K. Miyata, T. Watanabe, H. Fujikawa, R. Nakashima, A. Nasu, Y. Eto, N. Takahashi, H. Nohara, M. Ann Suico, S. Kotani, Y. Obata, Y. Sakamoto, Y. Seguchi, J. Saruwatari, T. Imafuku, H. Watanabe, T. Maruyama, H. Kai, T. Shuto
    • Journal Title

      Scientific reports

      Volume: 10 Issue: 1 Pages: 4313-4313

    • DOI

      10.1038/s41598-020-61148-2

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Circulating angiopoietin-like protein 2 levels and mortality risk in patients receiving maintenance hemodialysis: a prospective cohort study2019

    • Author(s)
      Morinaga J, Kakuma T, Fukami H, Hayata M, Uchimura K, Mizumoto T, Kakizoe Y, Miyoshi T, Shiraishi N, Adachi M, Izumi Y, Kuwabara T, Okadome Y, Sato M, Horiguchi H, Sugizaki T, Kadomatsu T, Miyata K, Tajiri S, Tajiri T, Tomita K, Kitamura K, Oike Y, Mukoyama M.
    • Journal Title

      Nephrology Dialysis Transplantation

      Volume: 印刷中 Issue: 5 Pages: 854-860

    • DOI

      10.1093/ndt/gfz236

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aging- and obesity-related peri-muscular adipose tissue accelerates muscle atrophy2019

    • Author(s)
      Zhu Shunshun、Tian Zhe、Torigoe Daisuke、Zhao Jiabin、Xie Peiyu、Sugizaki Taichi、Sato Michio、Horiguchi Haruki、Terada Kazutoyo、Kadomatsu Tsuyoshi、Miyata Keishi、Oike Yuichi
    • Journal Title

      PLOS ONE

      Volume: 14 Issue: 8 Pages: e0221366-e0221366

    • DOI

      10.1371/journal.pone.0221366

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity.2019

    • Author(s)
      Horiguchi H, Kadomatsu T, Kurahashi R, Hara C, Miyata K, Baba M, Osumi H, Terada K, Araki K, Takai T, Kamba T, Linehan WM, Moroishi T, Oike Y.
    • Journal Title

      Genes Dev

      Volume: 33 Issue: 23-24 Pages: 1641-1656

    • DOI

      10.1101/gad.329417.119

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] MiR-204-5p: a novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma.2019

    • Author(s)
      Kurahashi R, Kadomatsu T, Baba M, Hara C, Itoh H, Miyata K, Endo M, Morinaga J, Terada K, Araki K, Eto M, Schmidt LS, Kamba T, Linehan WM, Oike Y.
    • Journal Title

      Cancer Science

      Volume: 印刷中 Issue: 6 Pages: 1897-1908

    • DOI

      10.1111/cas.14026

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] The IncRNA Caren Protects Against Heart Failure by Inactivating the ATM-DNA Damage Response Pathway and Activating Mitochondrial Biogenesis2021

    • Author(s)
      Sato Michio, Keishi Miyata, Yuichi Oike
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2021 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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