Evaluation of cardiac function for DCM and HCM knock-in model mouse during early postnatal development
Project/Area Number |
16K08514
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
General physiology
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Research Institution | National Cardiovascular Center Research Institute |
Principal Investigator |
DU Cheng-Kun 国立研究開発法人国立循環器病研究センター, 研究所, 研究員 (90590646)
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Co-Investigator(Kenkyū-buntansha) |
森本 幸生 国際医療福祉大学, 福岡保健医療学部, 教授 (50202362)
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Research Collaborator |
Zhan Dong-Yun
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Project Period (FY) |
2016-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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Keywords | 心筋症 / モデル / 早期診断 / 心筋症モデル / 肥大型心筋症 / 早期治療 / 拡張型心筋症 / 心筋トロポニンT / ノックインマウス / 発症 / 突然死 / 心不全 / 循環器・高血圧 / 生理学 / シグナル伝達 / トランスレーショナルリサーチ |
Outline of Final Research Achievements |
HCM and DCM are often associated with severe heart failure and sudden death. Thus, early diagnosis and treatment is paramount for the reduction of its high mortality rate. The chief impetus of this study is to characterize the pathophysiology of knock-in mouse models of HCM and DCM. We showed that the S179F HCM mice developed left ventricular lumen narrowing and LV diastolic dysfunction before cardiac hypertrophy occured. The ΔK210 DCM mouse model developed LV systolic dysfunction and marked cardiac enlargement before LV wall became thinner. Further, ghrelin treatment (150 µg/kg/d s.c.) from fetal period has a benefit for attenuating cardiac remodeling and systolic dysfunction in the DCM mouse. Phenotypic changes in both mouse models occur at very early postnatal stage before weaning in the HCM and DCM mouse models. This suggests that these models are useful for the exploration of pathogenic mechanisms and therapeutics for very early onset HCM and DCM.
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Academic Significance and Societal Importance of the Research Achievements |
心筋症では、心筋トロポニンT(cTnT)などのサルコメア蛋白質において、様々な遺伝子変異が原因として同定されている。しかしながら、ヒト心筋症患者の病態を良く再現した動物モデルはこれまで殆どなかったため有効な治療法の開発が遅れている。我々は、マウスの内在性cTnT の特定部位にヒトDCMを発症させる変異ΔK210とHCMを発症させる変異S179Fを導入した二つのKI モデルの作製に成功した。本研究ではそれぞれの心筋症発症初期の病態形成に関する重要な知見が得られた。今後の若年突然死をはじめとする重要課題に対する理解や、心筋症の病態生理学に対して大きく貢献するものと考えられる。
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Report
(4 results)
Research Products
(23 results)
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[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.
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Journal Title
Sci Rep.
Volume: 7
Issue: 1
Pages: 9363-9363
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Tissue thrombin is associated with the pathogenesis of dilated cardiomyopathy.2016
Author(s)
Ito K, Hongo K, Date T, Ikegami M, Hano H, Owada M, Morimoto S, Kashiwagi Y, Katoh D, Yoshino T, Yoshii A, Kimura H, Nagoshi T, Kajimura I, Kusakari Y, Akaike T, Minamisawa S, Ogawa K, Minai K, Ogawa T, Kawai M, Yajima J, Matsuo S, Yamane T, Taniguchi I, Morimoto S, Yoshimura M.
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Journal Title
Int J Cardiol.
Volume: 228
Pages: 821-827
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Effects of Novel RyR2 Inhibitors on Diseased Hearts.2018
Author(s)
Nagomi Kurebayashi, Takashi Murayama, Mai Tamura, Shuichi Mori, Mari Yuasa-Ishigami, Hiroyuki Kagechika, Junji Suzuki, Kazunori Kanemaru, MasamitsuIino, SachioMorimoto, TakashiSakurai.
Organizer
63rd Annual Meeting of the Biophysical Society
Related Report
Int'l Joint Research
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