iPS cell-based modeling of inherited arrhythmia disorders using the latest genome editing technology
Project/Area Number |
19K17595
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 53020:Cardiology-related
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Research Institution | Kyoto University |
Principal Investigator |
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Project Period (FY) |
2019-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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Keywords | 不整脈 / iPS細胞 / 心臓突然死 / 遺伝子 / 遺伝性不整脈 / 突然死 / 心筋症 / 疾患モデル / ゲノム編集 / QT延長症候群 / 遺伝子不整脈 / ラミン関連心筋症 / 致死性遺伝性不整脈 |
Outline of Research at the Start |
本邦では年間5-10万人が心臓突然死をきたしていると推測され、致死性不整脈の原因としては、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例も存在し、遺伝子異常の関与が報告されている。本研究では、致死性遺伝性不整脈疾患の発症機序解明、治療法開発を目的とし、臨床・基礎研究を行う。特に、基礎研究では、患者由来人工多能性幹(iPS)細胞を用いた研究を遂行中だが、最近革新的な進歩を遂げている人工ヌクレアーゼを用いた最新のゲノム編集技術を用い、複数の変異を持つ複雑な症例に対しても適切なヒトiPS細胞由来心筋モデルを作成し、疾患表現型の再現、発症メカニズムの解明を行い、治療法開発を目指す。
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Outline of Final Research Achievements |
In this study, we aimed to analyze disease-specific iPS cell model using the latest genome editing technology in inherited arrhythmia disorders. We analyzed a case of QT prolongation syndrome and Brugada syndrome with a hetero-missense mutation (CACNA1C p.E1115K) in the cardiac L-type Ca2+ channel gene. As a control, we used an iPS cell line in which the mutation was corrected using the CRISPR-Cas9 system in patient-derived iPS cells. In the patient-derived iPS cell cardiomyocytes, mutant Ca2+ channels showed impaired ion selectivity, prolonged action potential duration, and decreased plateau phase. Thus, we successfully established an iPS cell model that reproduced the patient's clinical phenotypes.
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Academic Significance and Societal Importance of the Research Achievements |
遺伝性疾患患者由来iPS細胞モデルの解析に際して、コントロールとして健常人由来のiPS細胞のみの使用では、対象遺伝子変異以外の遺伝的背景が異なりその影響が除外できないという問題がある。本研究では、ゲノム編集技術を用いて変異をcorrectionさせたiPS細胞モデルをコントロールとすることにより対象変異が引き起こす変化を精密性の高い系を用いて解析した。また、ゲノム編集技術は、患者よりiPS細胞を作製できないケースやcompound変異等の解析にも有用であえう。ゲノム編集技術を用いたiPS細胞モデルは、病態解明、創薬研究への発展、患者診療への貢献が期待される。
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Report
(3 results)
Research Products
(30 results)
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[Presentation] Modeling Inherited Arrhythmias Associated with Ryanodine Receptor Dysfunction using iPS Cells2021
Author(s)
Takeru Makiyama, Jingshan Gao, Yuta Yamamoto, Asami Kashiwa, Takanori Aizawa, Tomohiko Imamura, Hai Huang, Hirohiko Kohjitani, Kouichi Kato, Taisuke Ishikawa, Hisaaki, Aoki, Futoshi Toyoda, Knut Wolten, Yoshinori Yoshida, Seiko Ohno, Naomasa Makita, Minoru Horie, Takeshi Kimura
Organizer
第85回日本循環器学会学術集会(JCS2021)
Related Report
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[Presentation] Development of an Oligonucleotide-Based Therapeutic Approach for Calmodulinopathy2021
Author(s)
Takeru Makiyama, Yuta Yamamoto, Yoshiki Kondo, Jingshan Gao, Asami Kashiwa, Takanori Aizawa, Tomohiko Imamura, Hai Huang, Hirohiko Kohjitani, Taisuke Ishikawa, Yoshinori Yoshida, Seiko Ohno, Naomasa Makita, Minoru Horie, Takeshi Kimura
Organizer
第85回日本循環器学会学術集会(JCS2021)
Related Report
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[Presentation] CALM2-N98S Mutation Associated with Long QT Syndrome Impaired the Response of KCNQ1 Channel to Beta-adrenergic Stimulation in Human iPSC-derived Cardiomyocytes.2020
Author(s)
Yuta Yamamoto, Takeru Makiyama, Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Huang Hai, Takanori Aizawa, Tomohiko Imamura, Taisuke Ishikawa, Hideki Motomura, Yoshinori Yoshida, Seiko Ohno, Minoru Horie, Naomasa Makita, Takeshi Kimura.
Organizer
第84回日本循環器学会学術集会(JCS2020)
Related Report
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[Presentation] Human Induced Pluripotent Stem Cell Model of CACNA1C-E1115K which Impairs Ion Selectivity of the Cardiac L-type Calcium Channel2020
Author(s)
Asami Kashiwa, Takeru Makiyama, Thomas Maurissen, Hirohiko Kohjitani, Yimin Wuriyanghai, Yuta Yamamoto, Jungshan Gao, Huang Hai, Tomohiko Imamura, Takanori Aizawa, Taisuke Ishikawa, Seiko Ohno, Futoshi Toyoda, Seiich Sato, Kazuhiro Takahashi, Knut Woltjen, Minoru Horie, Naomasa Makita, Takeshi Kimura.
Organizer
第84回日本循環器学会学術集会(JCS2020)
Related Report
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[Presentation] Preclinical Proof-of-concept of Antisense-mediated Transcript Knockdown Therapy in Calmodulinopathy2020
Author(s)
Yuta Yamamoto, Takeru Makiyama, Yoshiki Kondo, Yusuke Iriyama, Ryutarou Ishikawa, Jingshan Gao, Hirohiko Kohjitani, Asami Kashiwa, Takanori Aizawa, Tomohiko Imamura, Hai Huang, Taisuke Ishikawa, Yoshinori Yoshida, Seiko Ohno, Minoru Horie, Naomasa Makita, Takeshi Kimura.
Organizer
第14回日本循環器学会基礎研究フォーラム(BCVR2020)
Related Report
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[Presentation] 患者由来iPS細胞モデルを用いたCav 1.2イオン選択性を障害するCACNA1C-E1115K変異がQT延長症候群、Brugada症候群を発症するメカニズムの解析2020
Author(s)
Asami Kashiwa, Takeru Makiyama, Hirohiko Kohjitani, Thomas Maurissen, Yimin Wuriyanghai, Yuta Yamamoto, Jiungshan Gao, Huang Hai, Tomohiko Imamura, Takanori Aizawa, Taisuke Ishikawa, Seiko Ohno, Futoshi Toyoda, Seiich Sato, Kazuhiro Takahashi, Knut Woltjen, Minoru Horie, Naomasa Makita, Takeshi Kimura.
Organizer
第97回日本生理学会大会
Related Report
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[Presentation] Preclinical Proof-of-Concept Study: Antisense-mediated Knockdown of CALM as a Therapeutic Strategy for Calmodulinopathy2020
Author(s)
Yuta Yamamoto, Takeru Makiyama, Yoshiki Kondo, Yusuke Iriyama, Ryutarou Ishikawa, Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Huang Hai, Takanori Aizawa, Tomohiko Imamura, Taisuke Ishikawa, Yoshinori Yoshida, Seiko Ohno, Minoru Horie, Naomasa Makita, Takeshi Kimura
Organizer
European Society of Cardiology (ESC) Congress 2020
Related Report
Int'l Joint Research
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[Presentation] Inhibition of Late Sodium Current Attenuates Prolonged Action Potential Durations in CACNA1C-E1115K iPS Cell Model with Disrupted Cav1.2 ion Selectivity2020
Author(s)
Asami Kashiwa, Takeru Makiyama, Hirohiko Kohjitani, Thomas Maurissen, Yimin Wuriyanghai, Yuta Yamamoto, Jingshan Gao, Hai Huang, Tomohiko Imamura, Takanori Aizawa, Taisuke Ishikawa, Seiko Ohno, Futoshi Toyoda, Seiich Sato, Kazuhiro Takahashi, Knut Woltjen, Minoru Horie, Naomasa Makita, Takeshi Kimura
Organizer
The Heart Rhythm Society's Annual Scientific Sessions 2020 (HRS2020)
Related Report
Int'l Joint Research
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[Presentation] Clinical and genetic aspects of pediatric Brugada syndrome2020
Author(s)
Tomohiko Imamura, Takeru Makiyama, Hai Huang, Takanori Aizawa, Jingshan Gao, Asami Kashiwa, Yimin Wuriyanghai, Yuta Yamamoto, Yasuhiko Kohjitani, Koichi Kato, Seiko Ohno, Naokata Sumitomo, Minoru Horie.
Organizer
European Society of Cardiology (ESC) Congress 2020
Related Report
Int'l Joint Research
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[Presentation] Modeling Overlap Syndrome Of Long QT And Brugada Syndrome Associated With CACNA1C-E1115K Which Alters Ion Selectivity With Induced Pluripotent Stem Cells2019
Author(s)
Asami Kashiwa, Takeru Makiyama, Hirohiko Kohjitani, Yimin Wuriyanghai, Yuta Yamamoto, Gao Jungshan, Hai Huang, Taisuke Ishikawa, Seiko Ohno, Futoshi Toyoda, , Seiichi Sato, Minoru Horie , Naomasa Makita, Takeshi Kimura.
Organizer
40th Heart Rhythm Scientific Sessions
Related Report
Int'l Joint Research
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[Presentation] Automatic Computational Action Potential Analyzing System Enables Accurate Drug Response Interpretation and Prediction in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes2019
Author(s)
Hirohiko Kohjitani, Shigeya Kouda, Yukiko Himeno, Takeru Makiyama, Asami Kashiwa, Yimin Wuriyanghai, Yuta Yamamoto, Minoru Horie, Takeshi Kimura, Akinori Noma, Akira Amano.
Organizer
40th Heart Rhythm Scientific Sessions
Related Report
Int'l Joint Research
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[Presentation] Structural Insights into Catecholaminergic Polymorphic Ventricular Tachycardia-associated RyR2 Mutant Channels using a Three-dimensional In Silico Model.2019
Author(s)
J. Gao, T. Makiyama, S. Ohno, Y. Yamamoto, Y. Wuriyanghai, H. Kohjitani, A. Kashiwa, H. Huang, K. Katou, M. Horie, T. Kimura.
Organizer
European Society of Cardiology Congress 2019
Related Report
Int'l Joint Research
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[Presentation] KCNQ1 Channel Dysfunction in human induced pluripotent stem cell-derived cardiomyocytes carrying a CALM2-N98S mutation associated with long QT syndrome2019
Author(s)
Yuta Yamamoto, Takeru Makiyama, Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Huang Hai, Takanori Aizawa, Tomohiko Imamura, Taisuke Ishikawa, Seiko Ohno, Kazuhisa Chonabayashi, Hideki Motomura, Yoshinori Yoshida, Minoru Horie, Naomasa Makita, Takeshi Kimura
Organizer
American Heart Association Scientific Sessions 2019
Related Report
Int'l Joint Research
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[Presentation] Morphological and electrophysiological characterization of homozygous lamin A/C knockout human induced-pluripotent stem cell-derived cardiomyocytes. American Heart Association Scientific Sessions 20192019
Author(s)
Yimin Wuriyanghai, Takeru Makiyama, Yuta Yamamoto, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Hai Huang, Takanori Aizawa, Tomohiko Imamura, Seiko Ohno, Minoru Horie, Takeshi Kimura
Organizer
American Heart Association Scientific Sessions 2019
Related Report
Int'l Joint Research
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[Presentation] Response of KCNQ1 to Adrenergic Stimulation was Impaired in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes Carrying a CALM2-N98S Mutation Associated with Long QT Syndrome.2019
Author(s)
Yuta Yamamoto, Takeru Makiyama, Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Huang Hai, Takanori Aizawa, Tomohiko Imamura, Taisuke Ishikawa, Seiko Ohno, Kazuhisa Chonabayashi, Hideki Motomura, Yoshinori Yoshida, Minoru Horie, Naomasa Makita, Takeshi Kimura
Organizer
12th Asia Pacific Heart Rhythm Society Scientific Session (APHRS2019)
Related Report
Int'l Joint Research
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[Presentation] Algorithmic Auto-Recreation System of hiPSC-CMs Simulation and Prediction of Drug Testing.2019
Author(s)
Hirohiko Kohjitani, Shigeya Kouda, Yukiko Himeno, Takeru Makiyama, Asami Kashiwa, Yimin Wuriyanghai, Yuta Yamamoto, Minoru Horie, Takeshi Kimura, Akinori Noma, Akira Amano
Organizer
12th Asia Pacific Heart Rhythm Society Scientific Session (APHRS2019)
Related Report
Int'l Joint Research
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[Presentation] Patients characteristics of idiopathic ventricular fibrillation carrying SCN5A mutations without Brugada or long QT syndrome.2019
Author(s)
Takanori Aizawa, Takeru Makiyama, Hai Huang, Tomohiko Imamura, JingShan Gao, Yimin Wuriyanghai, Takeru Makiyama, Yuta Yamamoto, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Hai Huang, Wuriyanghai Yimin, Hirohiko Kohjitani, Yuta Yamamoto, Seiko Ohno, Minoru Horie
Organizer
12th Asia Pacific Heart Rhythm Society Scientific Session (APHRS2019)
Related Report
Int'l Joint Research
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[Presentation] Algorithmic Auto-Recreation System of hiPSC-CMs Simulation and Prediction of Drug Testing2019
Author(s)
Hirohiko Kohjitani, Shigeya Kouda, Yukiko Himeno, Takeru Makiyama, Hai Huang, Jingshan Gao, Asami Kashiwa, Yimin Wuriyanghai, Daisuke Yoshinaga, Takeshi Kimura, Akira Amano.
Organizer
第83回日本循環器学会学術集会
Related Report
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[Presentation] Modeling Overlapping Phenotypes of Long-QT and Brugada Syndrome with CACNA1C-E1115K that Alters Ion Selectivity of the Cardiac L-Type Calcium Channel Using Induced Pluripotent Stem Cells.2019
Author(s)
Asami Kashiwa, Takeru Makiyama, Hirohiko Kohjitani, Yimin Wuriyanghai, Yuta Yamamoto, Jingshan Gao, Hai Huang, Taisuke Ishikawa, Seiko Ohno, Futoshi Toyoda, Seiichi Sato, Minoru Horie, Naomasa Makita, Takeshi Kimura
Organizer
第66回日本不整脈心電学会学術大会
Related Report
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[Presentation] Algorithmic Auto-Recreation System of hiPSC-CMs Simulation and Prediction of Drug Testing.2019
Author(s)
Hirohiko Kohjitani, Shigeya Kouda, Yukiko Himeno, Takeru Makiyama, Hai Huang, Jingshan Gao, Asami Kashiwa, Yimin Wuriyanghai, Daisuke Yoshinaga, Takeshi Kimura, Akira Amano.
Organizer
第66回日本不整脈心電学会学術大会
Related Report
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[Presentation] Single Cell Electrophysiological Analysis of iPS Cell-derived Cardiomyocytes Generated from Long-QT Syndrome Patients Carrying a CALM2 Mutation Using a Membrane Potential Imaging System.2019
Author(s)
Yuta Yamamoto, Takeru Makiyama(代発表), Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Huang Hai, Taisuke Ishikawa, Seiko Ohno, Kazuhisa Chonabayashi, Kenji Suda, Yoshinori Yoshida, Minoru Horie, Naomasa Makita, Takeshi Kimura,
Organizer
第66回日本不整脈心電学会学術大会
Related Report
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[Presentation] Structural Insights into Catecholaminergic Polymorphic Ventricular Tachycardia-associated RyR2 Mutant Channels using a Three-dimensional in Silico Model.2019
Author(s)
Jingshan Gao, Takeru Makiyama, Seiko Ohno, Yuta Yamamoto, Yimin Wuriyanghai, Hirohiko Kohjitani, Asami Kashiwa, Hai Huang, Kouichi Katou, Minoru Horie, Takeshi Kimura.
Organizer
第66回日本不整脈心電学会学術大会
Related Report
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[Presentation] Phenotype-based High-throughput Classification of Long-QT Syndrome Subtypes Using Human Induced Pluripotent Stem Cells.2019
Author(s)
Daisuke Yoshinaga, Shiro Baba, Takeru Makiyama, Hirofumi Shibata, Takuya Hirata, Kentaro Akagi, Koichi Matsuda, Hirohiko Kohjitani, Yimin Wuriyanghai, Katsutsugu Umeda, Yuta Yamamoto, Bruce R. Conklin, Minoru Horie, Junko Takita, Toshio Heike.
Organizer
第66回日本不整脈心電学会学術大会
Related Report
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[Presentation] Complex aberrant splicing in the induce pluripotent stem cell-derived cardiomyocytes from a patient with long-QT syndrome carrying KCNQ1-A344Aspl mutation.2019
Author(s)
Wuriyanghai Y, Makiyama T, Sasaki K, Kamakura T, Yamamoto Y, Hayano M, Harita T, Nishiuchi S, Chen J, Kohjitani H, Hirose S, Yokoi F, Gao J, Chonabayashi K, Watanabe K, Ohno S, Yoshida Y, Kimura T, Horie M
Organizer
第66回日本不整脈心電学会学術大会
Related Report