Modeling Inherited Arrhythmia Disorders Using Patient-Derived Induced Pluripotent Stem Cells
Project/Area Number |
16K09499
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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 |
Cardiovascular medicine
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Research Institution | Kyoto University |
Principal Investigator |
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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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | 不整脈 / iPS細胞 / 遺伝子 / 突然死 / 心筋症 / 疾患モデル / 遺伝性不整脈 / QT延長症候群 / カルモジュリン / 遺伝子治療 / ゲノム編集 / 分子心臓学 / 生理学 / 薬理学 |
Outline of Final Research Achievements |
In this study, we performed clinical and basic researches based on the hereditary arrhythmia genome database to elucidate the genetic background of the familial arrhythmia disease (fatal inherited arrhythmia disorders). As main results, the truncation mutation carriers exhibited earlier development of cardiac disorders in comparison with missense mutation carriers in lamin A/C-related cardiomyopathy. In addition, we established iPS cell model of long-QT syndrome (LQT) type 1, calmodulin-related LQT (LQT15), and cardiac Na channelopathy. Using these models, we revealed the disease causing mechanisms and developed a novel gene therapy by mutant allele-specific knockout using the latest genome editing technology in LQT 15. Furthermore, we demonstrated the effectiveness of novel compounds in LQT1 iPS cell model which provides a new insight into tailor-made pharmacotherapy.
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Academic Significance and Societal Importance of the Research Achievements |
致死性遺伝性不整脈疾患は、明らかな基礎疾患がないにも関わらず心室細動を来たし突然死に至ることがあり、根本的な治療法は確立されておらず、社会的インパクトも大きい。ラミンA/C遺伝子関連心筋症に関しては、本研究にて得られた知見により、早期発症リスク患者に対する早期治療介入を考慮する重要な知見と考える。また、疾患特異的iPS細胞研究では、LQT15において最新のゲノム編集技術を用いた新規遺伝子治療法を提示し、学術的インパクトは大きいと考える。LQTに対する新規治療候補化合物の検討も行っており、遺伝型に応じた新規テーラーメード治療が開発されたあかつきには、診療、患者の生命予後改善に寄与できると考える。
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Report
(4 results)
Research Products
(65 results)
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[Journal Article] Allele-specific Ablation Rescues Electrophysiological Abnormalities in a Human iPS Cell Model of Long-QT Syndrome with a CALM2 Mutation2017
Author(s)
Yamamoto Y, Makiyama T*, Harita T, Sasaki K, Wuriyanghai Y, Hayano M, Nishiuchi S, Kohjitani H, Hirose S, Chen J, Yokoi F, Ishikawa T, Ohno S, Chonabayashi K, Motomura H, Yoshida Y, Horie M, Makita N, Kimura T
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Journal Title
Hum Mol Genet
Volume: -
Pages: -
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Patient-specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical PacingValidatesS107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia2016
Author(s)
Sasaki K, Makiyama T, Yoshida Y, Wuriyanghai Y, Kamakura T, Nishiuchi S, Hayano M, Harita T, Yamamoto Y, Kohjitani H, Hirose S, Chen J, Itoh H, Kawamura M, Ohno S, Takeuchi A, Matsuoka S, Miura M, Sumitomo N, Horie M, Yamanaka S, Kimura T
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Journal Title
PLoS One
Volume: 11(10)
Pages: -
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The genetics underlying acquired long QT syndrome: impact for genetic screening2016
Author(s)
Itoh H, Crotti L, Aiba T, Spazzolini C, Denjoy I, Fressart V, Hayashi K, Nakajima T, Ohno S, Makiyama T, Wu J, Hasegawa K, Mastantuono E, Dagradi F, Pedrazzini M, Yamagishi M, Berthet M, Murakami Y, Shimizu W, Guicheney P, Schwartz PJ, Horie M
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Journal Title
Eur Heart J
Volume: 37(18)
Pages: 1456-64
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] Significance of cell-specific precise computer simulation using new mathematical models of human induced pluripotent stem cell derived cardiomyocyte in drug testing2018
Author(s)
Hirohiko Kohjitani, Shigeya Kouda, Yukiko Himeno, Takeru Makiyama, Fumika Yokoi, Sayako Hirose, Yimin Wuriyanghai, Yuta Yamamoto, Minoru Horie, Takeshi Kimura, Akinori Noma, Akira Amano
Organizer
European Society of Cardiology Congress 2018
Related Report
Int'l Joint Research
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[Presentation] Analysis of Disease-Causing Mechanism of Lamin A/C-Related Cardiomyopathy Using Homozygous Lamin A/C Knock out Human Induced Pluripotent Stem Cell Model2018
Author(s)
Yimin Wuriyanghai, Takeru Makiyama, Yuta Yamamoto, Suguru, Nishiuchi, Sayako Hirose, Hirohiko Kohjitani, Jingshan Gao, Asami Kashiwa, Seiko Ohno, Minoru Horie, Takeshi Kimura
Organizer
The 11th Asia Pacific Heart Rhythm Society Scientific Session
Related Report
Int'l Joint Research
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[Patent(Industrial Property Rights)] 医薬組成物2016
Inventor(s)
堀江稔、牧山武、松浦博、豊田太、張田健志
Industrial Property Rights Holder
堀江稔、牧山武、松浦博、豊田太、張田健志
Industrial Property Rights Type
特許
Industrial Property Number
特願2016-250087
Filing Date
2016-12-22
Related Report