Role of a functional SNP of the gene coding brain serotonin synthesis rate-limiting enzyme Tph2 in dilated cardiomyopathy
Project/Area Number |
17K08540
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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 | International 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)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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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)
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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.
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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。
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Report
(4 results)
Research Products
(19 results)
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[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
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Journal Title
Scientific reports
Volume: 9
Issue: 1
Pages: 1-14
DOI
Related Report
Peer Reviewed / Open Access
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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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[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
Int'l Joint Research
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