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Elucidation of the irreversible mechanism of severe heart failure using biological monitoring murine heart failure model

Research Project

Project/Area Number 15K09139
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Cardiovascular medicine
Research InstitutionOsaka University

Principal Investigator

ASANO Yoshihiro  大阪大学, 大学院医学系研究科, 講師 (60527670)

Co-Investigator(Kenkyū-buntansha) 塚本 蔵  大阪大学, 医学系研究科, 助教 (80589151)
加藤 久和  大阪大学, 医学系研究科, 助教 (30589312)
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsエピゲノム / 細胞核クロマチン / 難治性心不全 / 分子循環器病学 / 臨床循環器
Outline of Final Research Achievements

Molecular biology and pathological analysis were performed to elucidate the molecular mechanism of refractory severe heart failure. We established our own epigenetic index analysis method for discrimination between irreversible and reversible cardiac muscle and investigated the molecular search and pathology of refractory heart failure. Imaging analysis technique by electron microscopic histopathology and quantitative evaluation method by automatic measurement of chromatin score were established and the severity of human heart failure was evaluated. Regarding the CR9 enhancer discovered by us, the mechanotransduction mechanism through CR9 activation was clarified, making it possible to stratify heart failure exacerbation using CR9-Tg mouse. It was suggested that development of new irreversible assessment index can be developed by expanding this research and carrying out human clinical observation research.

Academic Significance and Societal Importance of the Research Achievements

心不全の可逆性に関する組織学的マーカーとして、細胞核クロマチンスコア計測法を確立することで、エピジェネティック機序が心不全に関与することを示唆した研究である。加えて、心不全病態特異的遺伝子発現を示す代表的遺伝子BNP上流にある病態特異的エンハンサーCR9を同定し、動物モデルにおいてCR9エンハンサー活性を世界で初めて確認した。我々が作成したCR9遺伝子改変マウスは心不全を生体下にモニタリングできる心不全モデル動物である。心不全病態進展機序の解明として学術的に、心不全治療薬剤開発および心毒性有無の検証に利用可能な疾患モデル動物を開発したことから、社会・医療経済的にも意義がある研究となった。

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (21 results)

All 2018 2017 2016 2015

All Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 8 results,  Open Access: 7 results,  Acknowledgement Compliant: 4 results) Presentation (10 results) (of which Int'l Joint Research: 3 results,  Invited: 4 results) Book (3 results)

  • [Journal Article] Genetic basis of cardiomyopathy and the genotypes involved in prognosis and left ventricular reverse remodeling2018

    • Author(s)
      Tobita T, Nomura S, Fujita T, Morita H, Asano Y, Onoue K, Ito M, Imai Y, Suzuki A, Ko T, Satoh M, Fujita K, Naito AT, Furutani Y, Toko H, Harada M, Amiya E, Hatano M, Takimoto E, Shiga T, Nakanishi T, Sakata Y, Ono M, Saito Y, Takashima S, Hagiwara N, Aburatani H, Komuro I.
    • Journal Title

      Sci Rep

      Volume: 8 Issue: 1 Pages: 20114-20119

    • DOI

      10.1038/s41598-018-20114-9

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms2017

    • Author(s)
      Kondo H, Maksimova N, Otomo T*,Kato H, Imai A, Asano Y, Kobayashi K, Nojima S, Nakaya A, Hamada Y, Irahara K, Gurinova E, Sukhomyasova A, Nogovicina A, Savvina M, Yoshimori T, Ozono K Sakai N*
    • Journal Title

      Human Molecular Genetics

      Volume: 26 Pages: 173-183

    • DOI

      10.1093/hmg/ddw377

    • Related Report
      2017 Annual Research Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Sphingomyelin Phosphodiesterase 3 Enhances Cytodifferentiation of Periodontal Ligament Cells2017

    • Author(s)
      S Miyauchi, J Kitagaki, R Masumoto, A Imai, K Kobayashi, A Nakaya, S Kawai, C Fujihara, Y Asano, M Yamashita, M Yanagita, S Yamada, M Kitamura, S. Murakami
    • Journal Title

      J Dent Res

      Volume: 96 Issue: 3 Pages: 339-46

    • DOI

      10.1177/0022034516677938

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Novel Synthesized Radical-Containing Nanoparticles Limit Infarct Size Following Ischemia and Reperfusion in Canine Hearts.2017

    • Author(s)
      Asanuma H, Sanada S, Yoshitomi T, Sasaki H, Takahama H, Ihara M, Takahama H, Shinozaki Y, Mori H, Asakura M, Nakano A, Sugimachi M, Asano Y, Minamino T, Takashima S, Nagasaki Y, Kitakaze M.
    • Journal Title

      Cardiovasc Drugs Ther.

      Volume: 31 Issue: 5-6 Pages: 501-510

    • DOI

      10.1007/s10557-017-6758-6

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition.2016

    • Author(s)
      Ma J, Luo T, Zeng Z, Fu H, Asano Y, Liao Y, Minamino T, Kitakaze M.
    • Journal Title

      Sci Rep

      Volume: 6 Issue: 1 Pages: 34036-34036

    • DOI

      10.1038/srep34036

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A Putative Association of a Single Nucleotide Polymorphism in GPR126 with Aggressive Periodontitis in a Japanese Population2016

    • Author(s)
      Kitagaki J, Miyauchi S, Asano Y, Imai A, Kawai S, Michikami I, Yamashita M, Yamada S, Kitamura M, Murakami S
    • Journal Title

      PLoS One

      Volume: 11 Issue: 8 Pages: e0160765-e0160765

    • DOI

      10.1371/journal.pone.0160765

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA.2016

    • Author(s)
      Masumura Y, Higo S, Asano Y, Kato H, Yan Y, Ishino S, Tsukamoto O, Kioka H, Hayashi T, Shintani Y, Yamazaki S, Minamino T, Kitakaze M, Komuro I, Takashima S, Sakata Y.
    • Journal Title

      Sci Rep.

      Volume: 6 Issue: 1 Pages: 28592-28592

    • DOI

      10.1038/srep28592

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] A Development of Nucleic Chromatin Measurements as a New Prognostic Marker for Severe Chronic Heart Failure.2016

    • Author(s)
      Kanzaki M, Asano Y, Ishibashi-Ueda H, Oiki E, Nishida T, Asanuma H, Kato H, Oka T, Ohtani T, Tsukamoto O, Higo S, Kioka H, Matsuoka K, Sawa Y, Komuro I, Kitakaze M, Takashima S, Sakata Y.
    • Journal Title

      PLoS One.

      Volume: 11 Issue: 2 Pages: e0148209-e0148209

    • DOI

      10.1371/journal.pone.0148209

    • Related Report
      2016 Research-status Report 2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] プレナリーセッション:多層化する循環器ゲノム研究(Multilayered Cardiovascular Genetics) Clinical Application of Whole Exome Sequencing inSinus Bradycardia and a Strategy for Development of aNovel Targeted Therapy2018

    • Author(s)
      朝野仁裕
    • Organizer
      第82回日本循環器学会学術集会
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 教育セッション:ゲノム診療が循環器医に求めるもの2017

    • Author(s)
      朝野仁裕
    • Organizer
      第123回日本循環器学会近畿地方会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 特別講演:「次世代シークエンサーから見えてくる循環器疾患の病態」 循環器希少難病に対する疾患ゲノム解析の実際と臨床応用2017

    • Author(s)
      朝野仁裕
    • Organizer
      第20回小児心血管分子医学研究会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] BNPエンハンサー領域に着目した新規心毒性評価系の開発2017

    • Author(s)
      宮下洋平、朝野仁裕
    • Organizer
      Molecular Cardiovascular Metabolic Conference
    • Related Report
      2017 Annual Research Report
  • [Presentation] De novo BNP enhancer region (CR9) works as the mechanical stress-responsive element of Nppb2017

    • Author(s)
      宮下洋平、朝野仁裕
    • Organizer
      第1回日本循環器学会基礎研究フォーラム
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 心筋症症例の全エクソームシーケンスによる疾患変異解析(Genetic Analysis for a Cardiomyopathy population with Whole Exome Sequencing)2017

    • Author(s)
      多久和綾子、朝野仁裕
    • Organizer
      第62回日本人類遺伝学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 心筋症のエクソーム解析による原因変異検索2017

    • Author(s)
      多久和綾子、朝野仁裕
    • Organizer
      第40回 日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 難治性遺伝性循環器疾患における全エクソーム解析と家系症例に対する臨床遺伝子診断の試み2016

    • Author(s)
      朝野仁裕
    • Organizer
      第20回日本心不全学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2016-10-08
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 教育セッション(6)「臨床医が学ぶ基礎医学講座」 「疾患ゲノム解析の進化と臨床への応用」2015

    • Author(s)
      朝野仁裕
    • Organizer
      第19回日本心不全学会学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2015-10-24
    • Related Report
      2015 Research-status Report
    • Invited
  • [Presentation] 心筋症の遺伝子・分子医学・基礎と臨床「遺伝性心筋症における新たなゲノム情報解析による変異同定法の開発」2015

    • Author(s)
      朝野仁裕
    • Organizer
      第1回心筋症研究会
    • Place of Presentation
      東京
    • Year and Date
      2015-07-04
    • Related Report
      2015 Research-status Report
    • Invited
  • [Book] 「ここが知りたい、強心薬のさじ加減」 急性心不全:4章:「強心薬の効果が十分でない時の対応」2016

    • Author(s)
      朝野仁裕
    • Publisher
      中外医学社
    • Related Report
      2015 Research-status Report
  • [Book] 「重症心不全の患者さんが来ました」 第10章:「遺伝子」2016

    • Author(s)
      朝野仁裕
    • Publisher
      中外医学社
    • Related Report
      2015 Research-status Report
  • [Book] 最新医学 別冊 診断と治療のABC 「心不全」 第2章 病態・病態生理、心筋症の原因遺伝子2015

    • Author(s)
      朝野仁裕
    • Publisher
      最新医学社
    • Related Report
      2015 Research-status Report

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Published: 2015-04-16   Modified: 2021-12-27  

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