Elucidation of pathophysiological mechanisms and the development of innovative therapies for lethal arrhythmias caused by calmodulin mutations
Project/Area Number |
18K15847
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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 |
Yamamoto Yuta 京都大学, 医学研究科, 研究員 (10802762)
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Project Period (FY) |
2018-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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Keywords | カルモジュリン / 不整脈 / iPS細胞 / QT延長症候群 / アンチセンス核酸 / 遺伝子治療 / アンチセンス / 遺伝性心疾患 |
Outline of Final Research Achievements |
Recently, mutations in CALM genes (CALM1-3) encoding calmodulin (CaM) are reported to be associated with severe early-onset arrhythmias known as the calmodulinopathy. However, the pathophysiological mechanisms of calmodulinopathy remains unknown. Moreover, there is no effective treatment for calmodulinopathy. In the present study, we analyzed KCNQ1 channel function using patch clamp technique and elucidate the KCNQ1 channel dysfunction using human iPS cell model that may explain the clinical phenotype of the LQTS patient carrying the CALM2-N98S mutation. In addition, we demonstrated that antisense oligonucleotides-based therapy might be a promising strategy for the treatment of calmodulinopathy.
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Academic Significance and Societal Importance of the Research Achievements |
カルモジュリン関連不整脈疾患は若年発症で重篤な症状を引き起こすことが知られているが、その詳細な発症機序は不明な点が多く、有効な治療法も確立されておらず、本疾患の病態を解明し、新規治療法を開発する社会的な意義は大きい。本研究によりCALM2-N98S変異において、KCNQ1チャネルの機能障害を明らかにしたが、これは実際の治療法の選択に関して重要な知見であると考えられる。また、これまでの治療法とは異なりアンチセンス核酸を用いた治療法は変異カルモジュリンをターゲットとした全く新しい治療法であり、本質的な治療となる可能性があり、学術的意義は大きいと考える。
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Report
(3 results)
Research Products
(32 results)
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[Journal Article] Clinical Manifestations and Long-Term Mortality in <i>Lamin A/C</i> Mutation Carriers From a Japanese Multicenter Registry2018
Author(s)
14.Nakajima K, Aiba T, Makiyama T, Nishiuchi S, Ohno S, Kato K, Yamamoto Y, Doi T, Shizuta S, Onoue K, Yagihara N, Ishikawa T, Watanabe I, Kawakami H, Oginosawa Y, Murakoshi N, Nogami A, Aonuma K, Saito Y, Kimura T, Yasuda S, Makita N, Shimizu W, Horie M, Kusano K.
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Journal Title
Circulation Journal
Volume: 82
Issue: 11
Pages: 2707-2714
DOI
NAID
ISSN
1346-9843, 1347-4820
Year and Date
2018-10-25
Related Report
Peer Reviewed / Open Access
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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
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