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Knock-in mouse model of hypertrophic cardiomyopathy caused by troponin T mutation

Research Project

Project/Area Number 24790791
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Circulatory organs internal medicine
Research InstitutionNational Cardiovascular Center Research Institute

Principal Investigator

DU Cheng-Kun  独立行政法人国立循環器病研究センター, 研究所, 研究員 (90590646)

Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords肥大型心筋症 / ノックインマウス / 突然死 / 心筋トロポニンT / 遺伝子変異 / カルシウム感受性 / ノックイン / マウス / 発症メカニズム / 心筋トロポニン / ミューテーション / トロポニン / ノックインモデル
Outline of Final Research Achievements

We created knock-in mice with a missense mutation S179F in cardiac troponin T (cTnT), which had been found to be associated with human hypertrophic cardiomyopathy (HCM). Membrane-permeabilized cardiac muscle fibers from these mice showed significantly higher Ca2+ sensitivity in force generation than those from wild-type mice. The knock-in mice suffered from sudden death frequ ently, and histological examination of cardiac sections showed significant displacement fibrosis, myocardial hypertrophy, and myocyte disarray. Echocardiography showed that left ventricular (LV) end-diastolic dimension was significantly decreased with no changes in ejection fraction. In vivo cardiac catheter measurements showed a significant increase in LVdP/dtmin with no changes in LVdP/dtmax. These results indicate that the knock-in mouse with S179F mutation in cTnT is a useful mouse model of HCM closely capitulating the clinical phenotypes of human patients.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (23 results)

All 2015 2014 2013 2012

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 3 results,  Acknowledgement Compliant: 3 results) Presentation (16 results)

  • [Journal Article] In vivo effects of propyl gallate, a novel Ca(2+) sensitizer, in a mouse model of dilated cardiomyopathy caused by cardiac troponin T mutation.2014

    • Author(s)
      Cheng-Kun Du, Dong-Yun Zhan, Sachio Morimoto
    • Journal Title

      Life Sciences

      Volume: 109 Issue: 1 Pages: 15-19

    • DOI

      10.1016/j.lfs.2014.06.004

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Survival benefit of ghrelin in the heart failure due to dilated cardiomyopathy2014

    • Author(s)
      Cheng-Kun Du, Dong-Yun Zhan, Sachio Morimoto, Tsuyoshi Akiyama, Daryl O. Schwenke, Hiroshi Hosoda, Kenji Kangawa, Mikiyasu Shirai
    • Journal Title

      Pharmacology Research & Perspectives

      Volume: 2 Issue: 5

    • DOI

      10.1002/prp2.64

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Myocardial interstitial levels of serotonin and its major metabolite, 5-hydroxyindole acetic acid, in in vivo rat heart2014

    • Author(s)
      Cheng-Kun Du, Dong-Yun Zhan, Tsuyoshi Akiyama, Takashi Sonobe, Tadakatsu Inagaki, Mikiyasu Shirai
    • Journal Title

      Life Sciences

      Volume: 117 Issue: 1 Pages: 33-39

    • DOI

      10.1016/j.lfs.2014.09.019

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Contribution of calpain to myoglobin efflux from cardiomyocytes during icehemia and after reperfusion in anesthetized rats.2014

    • Author(s)
      Sonobe T, Akiyama T, Du CK, Zha n DY, Shirai M.
    • Journal Title

      Acta Physiol

      Volume: 210(4) Issue: 4 Pages: 823-831

    • DOI

      10.1111/apha.12205

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] In vivo monitoring of acetylcholine release from cardiac vagal nerve endings in anaesthetized mice.2013

    • Author(s)
      Zhan DY, Du CK, Akiyama T, Sonobe T, Tsuchimochi H, Shirai M.
    • Journal Title

      Auton Neurosci

      Volume: 176(1-2) Issue: 1-2 Pages: 91-94

    • DOI

      10.1016/j.autneu.2013.02.014

    • Related Report
      2013 Research-status Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Contribution of serotonin uptake and degradation to myocardial interstitial seroton in levels during ischaemia-reperfusion in rabbits.2013

    • Author(s)
      Sonobe T, Akiyama T, Du CK, Zhan DY, Shirai M.
    • Journal Title

      Acta Physiol (Oxf).

      Volume: 207 Issue: 2 Pages: 260-268

    • DOI

      10.1111/j.1748-1716.2012.02461.x

    • Related Report
      2013 Research-status Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Role of brain serotonin dysfunction in the pathophysiology of congestive heart failure2012

    • Author(s)
      Li L, Morimoto S, Take S, Zhan D.-Y, Du C.-K, Wang Y.-Y, Fan X.-L, Yoshihara T, Takahashi-Yanaga F, Katafuchi T, Sasaguri T
    • Journal Title

      J Mol Cell Cardiol

      Volume: 53 Issue: 6 Pages: 760-767

    • DOI

      10.1016/j.yjmcc.2012.08.006

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] Knock-in mouse model of hypertrophic cardiomyopathy caused by troponin T mut2015

    • Author(s)
      Cheng-Kun Du, Dong-Yun Zhan, Sachio Morimoto, Mikiyasu Shirai
    • Organizer
      The 120th Annual Meeting of The Japanese Association of Anatomists
    • Place of Presentation
      神戸国際会議場・展示場
    • Year and Date
      2015-03-21 – 2015-03-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] Survival benefit of ghrelin in the heart failure due to dilated cardiomyopat2015

    • Author(s)
      Dong-Yun Zhan, Cheng-Kun Du, Sachio Morimoto, Tsuyoshi Akiyama, Daryl O. Schwenke, Hiroshi Hosoda, Kenji Kangawa, Mikiyasu Shirai
    • Organizer
      The 120th Annual Meeting of The Japanese Association of Anatomists
    • Place of Presentation
      神戸国際会議場・展示場
    • Year and Date
      2015-03-21 – 2015-03-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] Role of monoamine oxidase on hydroxyl radical production during ischemia/reperfusion in anesthetized rats2015

    • Author(s)
      Tadakatsu Inagaki, Tsuyoshi Akiyama, Dong-Yun Zhan, Cheng-Kun Du, Mikiyasu Shirai
    • Organizer
      The 120th Annual Meeting of The Japanese Association of Anatomists
    • Place of Presentation
      神戸国際会議場・展示場
    • Year and Date
      2015-03-21 – 2015-03-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] 心筋トロポニンT突然変異による肥大型心筋症ノックインマウスモデル2015

    • Author(s)
      杜 成坤、 戦 冬雲、 森本 幸生、 白井 幹康
    • Organizer
      第88回日本薬理学会年会
    • Place of Presentation
      名古屋国際会議場
    • Year and Date
      2015-03-18 – 2015-03-20
    • Related Report
      2014 Annual Research Report
  • [Presentation] 中枢を介した迷走神経活性化による拡張型心筋症治療薬2015

    • Author(s)
      戦 冬雲、 杜 成坤、 秋山 剛、 白井 幹康
    • Organizer
      第88回日本薬理学会年会
    • Place of Presentation
      名古屋国際会議場
    • Year and Date
      2015-03-18 – 2015-03-20
    • Related Report
      2014 Annual Research Report
  • [Presentation] Myocardial Interstitial Serotonin and its Major Metabolite, 5-Hydroxyindole Acetic Acid Levels Determined by Microdialysis Technique in vivo Rat Heart2015

    • Author(s)
      Cheng-Kun Du, Dong-Yun Zhan, Tsuyoshi Akiyama, Takashi Sonobe, Tadakatsu Inagaki, Mikiyasu Shirai
    • Organizer
      Biophysical Society 59th Annual Meeting
    • Place of Presentation
      Baltimore, Maryland, USA
    • Year and Date
      2015-02-07 – 2015-02-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] The Treatment Benefit of Ghrelin on a Mouse Model of Inherited Dilated2015

    • Author(s)
      Dong-Yun Zhan, Cheng-Kun Du, Sachio Morimoto, Tsuyoshi Akiyama, Daryl O. Schwenke, Hiroshi Hosoda, Kenji Kangawa, Mikiyasu Shirai
    • Organizer
      Biophysical Society 59th Annual Meeting
    • Place of Presentation
      Baltimore, Maryland, USA
    • Year and Date
      2015-02-07 – 2015-02-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] 拡張型心筋症ノックインモデルマウスに対するグレリンの治療効果2013

    • Author(s)
      杜 成坤, 戦 冬雲, 森本 幸生, 秋山 剛, 寒川 賢治, 白井 幹康
    • Organizer
      第17回日本心血管内分泌代謝学会学術総会
    • Place of Presentation
      大阪
    • Related Report
      2013 Research-status Report
  • [Presentation] うっ血性心不全の病態生理学における脳セロトニン機能障害の役割2013

    • Author(s)
      李 蕾, 森本 幸生, 武 幸子, 戦 冬雲, 杜 成坤, 王 媛媛, 範 雪麗, 片渕 俊彦、笹栗 俊之
    • Organizer
      第17回日本心血管内分泌代謝学会学術総会
    • Place of Presentation
      大阪
    • Related Report
      2013 Research-status Report
  • [Presentation] 虚血/再灌流における心筋間質セロトニンの動態2013

    • Author(s)
      杜 成坤, 戦 冬雲, 秋山 剛, 稲垣 薫克, 白井 幹康
    • Organizer
      第91回日本生理学会大会
    • Place of Presentation
      鹿児島
    • Related Report
      2013 Research-status Report
  • [Presentation] DCMノックインマウスにおける心臓迷走神経調節機構2013

    • Author(s)
      戦 冬雲, 杜 成坤, 秋山 剛, 森本 幸生, 清水 秀二, 川田 徹, 白井 幹康
    • Organizer
      第91回日本生理学会大会
    • Place of Presentation
      鹿児島
    • Related Report
      2013 Research-status Report
  • [Presentation] 稲垣 薫克, 秋山 剛, 戦 冬雲, 杜 成坤, 白井 幹康2013

    • Author(s)
      4-HBAを用いた心筋虚血再灌流時のヒドロキシラジカル測定
    • Organizer
      第91回日本生理学会大会
    • Place of Presentation
      鹿児島
    • Related Report
      2013 Research-status Report
  • [Presentation] 虚血/再灌流における心筋間質セロトニンの動態2013

    • Author(s)
      杜 成坤, 戦 冬雲, 秋山 剛, 稲垣 薫克, 白井 幹康
    • Organizer
      第87 回日本薬理学会年会
    • Place of Presentation
      仙台
    • Related Report
      2013 Research-status Report
  • [Presentation] DCMノックインマウスにおける心臓迷走神経調節機構2013

    • Author(s)
      戦 冬雲, 杜 成坤, 秋山 剛, 森本 幸生, 清水 秀二, 川田 徹, 白井 幹康
    • Organizer
      第87 回日本薬理学会年会
    • Place of Presentation
      仙台
    • Related Report
      2013 Research-status Report
  • [Presentation] マウス心臓交感神経終末におけるノルエピネフリン動態の解析―マイクロダイアリシス法を用いて―2013

    • Author(s)
      戦冬雲、杜成坤、秋山剛、曽野部崇、白井幹康
    • Organizer
      日本生理学会年会
    • Place of Presentation
      タワーホール船堀
    • Related Report
      2012 Research-status Report
  • [Presentation] うっ血性心不全の病態生理学における脳セロトニン機能障害の役割2013

    • Author(s)
      李 蕾、森本 幸生、武 幸子、戦 冬雲、杜 成坤、王 媛媛、範 雪麗、吉原 達也、高橋 富美、片渕 俊彦、笹栗 俊之
    • Organizer
      日本薬理学会年会
    • Place of Presentation
      福岡国際会議場
    • Related Report
      2012 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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