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Role of a functional SNP of the gene coding brain serotonin synthesis rate-limiting enzyme Tph2 in dilated cardiomyopathy

Research Project

Project/Area Number 17K08540
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General physiology
Research InstitutionInternational University of Health and Welfare

Principal Investigator

Morimoto Sachio  国際医療福祉大学, 福岡保健医療学部, 教授 (50202362)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords遺伝性拡張型心筋症 / ノックインマウス / 脳セロトニン機能 / 心臓突然死 / 心不全死 / ノックインマウスモデル / 重症心不全死
Outline of Final Research Achievements

Tryptophan hydroxylase 2 (TPH2) expressed specifically in the central nervous system is involved in serotonin synthesis in the brain as a rate-limiting enzyme. Inbred mice have a functional SNP C1473G in Tph2, with the activity being lower in BALB/c with G/G allele than in C57BL/6 with C/C allele. In this study, we examined the role of this SNP in the disease phenotype of knock-in mice with a dilated cardiomyopathy (DCM)-causing mutation deltaK210 in cTnT by creating single-gene congenic strain with Tph2 1473C/C or G/G allele. C57BL/6 DCM mice frequently suffered from sudden cardiac death (SCD) with no heart failure symptoms, whereas BALB/c DCM mice mostly died of congestive HF. Introduction of G/G allele into C57BL/6 DCM mice caused congestive HF death and extended the life expectancy. On the other hand, introduction of C/C allele into BALB/c DCM mice caused SCD. Present results suggest that brain serotonin function plays an important role in the disease phenotype of DCM.

Academic Significance and Societal Importance of the Research Achievements

「脳セロトニン機能がDCM疾患表現型に影響する可能性がある」というのは以前の薬理学的研究(Li et al. J Mol Cell Cardiol, 2012)から導いた我々独自の仮説である。本研究は、近交系マウスに存在する活性の異なるセロトニン合成律速酵素Tph2の遺伝子多型を利用してこの仮説をさらに支持する新たな科学的証拠を提供するものである。本研究の成果は心不全および心臓突然死の精神的な面からの予防法開発や心理的ストレスが心疾患を誘発するメカニズムの解明などに役立つものであると期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (19 results)

All 2020 2019 2018 2017

All Journal Article (5 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (13 results) (of which Int'l Joint Research: 7 results,  Invited: 2 results) Book (1 results)

  • [Journal Article] Blockade of L-type Ca2+ channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway.2019

    • Author(s)
      Ikeda S, Matsushima S, Okabe K, Ikeda M, Ishikita A, Tadokoro T, Enzan N, Yamamoto T, Sada M, Deguchi H, Morimoto S, Ide T, Tsutsui H
    • Journal Title

      Scientific reports

      Volume: 9 Issue: 1 Pages: 1-14

    • DOI

      10.1038/s41598-019-46367-6

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Overexpression of heart-specific small subunit of myosin light chain phosphatase results in heart failure and conduction disturbance2018

    • Author(s)
      Arimura Takuro、Muchir Antoine、Kuwahara Masayoshi、Morimoto Sachio、Ishikawa Taisuke、Du Cheng-Kun、Zhan Dong-Yun、Nakao Shu、Machida Noboru、Tanaka Ryo、Yamane Yoshihisa、Hayashi Takeharu、Kimura Akinori
    • Journal Title

      American Journal of Physiology-Heart and Circulatory Physiology

      Volume: epub Issue: 6 Pages: H1192-H1202

    • DOI

      10.1152/ajpheart.00696.2017

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cardiotonic actions of quercetin and its metabolite tamarixetin through a digitalis-like enhancement of Ca 2+ transients2018

    • Author(s)
      Hayamizu Kengo、Morimoto Sachio、Nonaka Miki、Hoka Sumio、Sasaguri Toshiyuki
    • Journal Title

      Archives of Biochemistry and Biophysics

      Volume: 637 Pages: 40-47

    • DOI

      10.1016/j.abb.2017.11.009

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] CaMKII-mediated phosphorylation of RyR2 plays a crucial role in aberrant Ca 2+ release as an arrhythmogenic substrate in cardiac troponin T-related familial hypertrophic cardiomyopathy2018

    • Author(s)
      Okuda Shinichi、Sufu-Shimizu Yoko、Kato Takayoshi、Fukuda Masakazu、Nishimura Shigehiko、Oda Tetsuro、Kobayashi Shigeki、Yamamoto Takeshi、Morimoto Sachio、Yano Masafumi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 496 Issue: 4 Pages: 1250-1256

    • DOI

      10.1016/j.bbrc.2018.01.181

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Targeted Genome Replacement via Homology-directed Repair in Non-dividing Cardiomyocytes2017

    • Author(s)
      Ishizu T, Higo S, Masumura Y, Kohama Y, Shiba M, Higo T, Shibamoto M, Nakagawa A, Morimoto S, Takashima S, Hikoso S, Sakata Y.
    • Journal Title

      Sci Rep.

      Volume: 7 Issue: 1 Pages: 9363-9363

    • DOI

      10.1038/s41598-017-09716-x

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Role of a Functional SNP of the Gene Coding Brain Serotonin Synthesis Rate-Limiting Enzyme Tph2 in Dilated Cardiomyopathy2020

    • Author(s)
      Sachio Morimoto, Kengo Hayamizu, Miki Nonaka, Lei Li, Yuanyuan Wang
    • Organizer
      Biophysical Society
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Effects of RyR2 Inhibitors on Ca2+ Signals in Healthy and Diseased Cardiac Cells2020

    • Author(s)
      Nagomi Kurebayashi, Takashi Murayama, Masato Konishi, Shuichi Mori, Mari Ishigami-Yuasa, Hiroyuki Kagechika, Haruo Ogawa, Sachio Morimoto
    • Organizer
      Biophysical Society
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 拡張型心筋症モデルマウスにおける性差による自発運動の効果の違い2020

    • Author(s)
      杉原 匡美, 柿木 亮, 村山 尚, 三井田 孝, 櫻井 隆, 森本 幸生, 呉林 なごみ
    • Organizer
      日本薬理学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 拡張型心筋症における脳セロトニン合成律速酵素Tph2遺伝子機能的多型の役割2020

    • Author(s)
      森本 幸生,早水 憲吾
    • Organizer
      日本生理学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 遺伝性肥大型心筋症ノックインマウスモデルの出生後早期の病態2020

    • Author(s)
      杜 成坤, 戦 冬雲, 森本 幸生, 秋山 剛, 白井 幹康, Pearson James
    • Organizer
      日本生理学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ヒト拡張型心筋症ノックインマウスモデルの出生後早期における心機能評価2019

    • Author(s)
      杜 成坤、戦 冬雲、森本 幸生、秋山 剛、白井 幹康、Pearson James
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 毎日の自発運動は拡張型心筋症モデルマウスにおける心不全進行を抑制する2019

    • Author(s)
      杉原 匡美、柿木 亮、村山 尚、三井田 孝、櫻井 隆、森本 幸生、呉林 なごみ
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] The Effects of Frequency of Voluntary Exercise on Cardiac Function in Dilated Cardiomyopathy Model Mice2019

    • Author(s)
      Masami Sugihara, Ryo Kakig, Takashi Murayama, Takashi Miida, Takashi Sakurai, Sachio Morimoto, Nagomi Kurebayashi
    • Organizer
      2019 Biophysical Society Annual Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effects of Novel RyR2 Inhibitors on Diseased Hearts2019

    • Author(s)
      Nagomi Kurebayashi, Murayama, Mai Tamura, Shuichi Mori, Mari Yuasa-Ishigami, Hiroyuki Kagechika, Junji Suzuki, Kazunori Kanemaru, Masamitsu IIno, Sachio Morimoto,Takashi Sakurai,
    • Organizer
      2019 Biophysical Society Annual Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ミオフィラメントCa感受性と遺伝性心筋症2018

    • Author(s)
      森本 幸生
    • Organizer
      CVMW2018心血管代謝週間
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 若年性拡張型心筋症の初期 進行因子にカテコラミンは関 わるか? ーDCMモデルマウスによる検 討ー2018

    • Author(s)
      南沢 享 、谷端 淳 、藤本 義隆、森本 幸生
    • Organizer
      日本心不全学会第4回日本心筋症研究会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Relation between Voluntary Exercise Frequency and Cardiac Function in Dilated Cardiomyopathy Model Mice2018

    • Author(s)
      Sugihara M, Kakigi R, Murayama T, Miida T,. Sakura T, Morimoto S, Kurebayash N
    • Organizer
      2nd Annual Meeting of the Biophysical Society
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cardiotonic actions of quercetin and its metabolite tamarixetin through a digitalis-like enhancement of Ca 2+ transients2018

    • Author(s)
      Hayamizu K, Nonaka M, Morimoto S
    • Organizer
      2nd Annual Meeting of the Biophysical Society
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Book] 心不全 : 最新の基礎・臨床研究の進歩2018

    • Author(s)
      杜 成坤、森本 幸生
    • Total Pages
      715
    • Publisher
      日本臨牀社
    • Related Report
      2018 Research-status Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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