2021 Fiscal Year Final Research Report
Elucidation of the pathogenesis of lethal inherited arrhythmias using iPS cells and development of therapeutic approaches
| Project/Area Number |
19K08538
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 不整脈 / iPS細胞 / 遺伝子 / 心筋細胞 / 疾患モデル |
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| Outline of Final Research Achievements |
In this study, we aimed to elucidate the pathogenesis of inherited arrhythmias and to develop therapeutic methods, using disease-specific iPS cells (iPSCs). We identified a de novo heterozygous mutation, CALM2 p.E46K in a catecholaminergic polymorphic ventricular tachycardia (CPVT) patient who suffered exercise-induced syncope with ventricular tachycardias. CALM2-E46K iPSC-cardiomyocytes (CMs) exhibited significantly higher frequency of triggered activities and abnormal Ca2+ release events than controls. Larger Ca2+ leak via cardiac ryanodine receptors (RyR2) and smaller Ca2+ storage in sarcoplasmic reticulum observed in E46K-iPSC-CMs. Furthermore, we revealed a dominant facilitative effect of E46K-CaM on RyR2 using biochemical analyses. Thus, we, for the first time, established a CALM-related CPVT iPSC model which successfully recapitulated severe arrhythmogenic features and the iPSC model provides a powerful platform in developing precision medicine.
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| Free Research Field |
循環器内科
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| Academic Significance and Societal Importance of the Research Achievements |
遺伝性致死性不整脈疾患は器質的心疾患のない若年者にも突然死を来し得り、社会的影響が大きく、根本的な治療法が確立されていない。本研究対象のカルモジュリン変異による遺伝性不整脈疾患は、稀ではあるが非常に重篤な不整脈を呈する。我々は、カルモジュリン変異によるカテコラミン誘発性多形性心室頻拍のiPS細胞モデルを初めて確立し、重度の催不整脈性を再現することに成功した。また、本モデルを用いた薬効評価の知見は治療法に関するアンメット・メディカル・ニーズが大きい本疾患において臨床的に大きな意義があると考えられ、今後の新規治療法開発の強力なプラットフォームとなり精密医療への貢献が期待される。
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