Multidisciplinary approach to cardiac arrhythmogenesis assessment during drug discovery
| Project/Area Number |
15H04684
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | University of Shizuoka (2016-2018)
Tokyo Medical and Dental University (2015) |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
諫田 泰成 国立医薬品食品衛生研究所, 薬理部, 部長 (70510387)
芦原 貴司 滋賀医科大学, 医学部, 講師 (80396259)
児玉 昌美 東京医科歯科大学, 難治疾患研究所, 非常勤講師 (30512248)
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| Research Collaborator |
Okada Junichi
Nakai Yuji
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2017: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2016: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2015: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
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| Keywords | 薬理学 / イオンチャネル / 不整脈 / 心不全 / iPS細胞 / シミュレーション / ヒトiPS細胞 / インシリコモデル / 統合的解析 / 不整脈トリガー / 生理学 / 薬学 / 循環器・高血圧 / 心臓安全性 / 画像処理 / 抗がん剤 / 循環器･高血圧 |
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| Outline of Final Research Achievements |
In this study, we integrated technologies using human iPS cells and computer simulations, and aimed to accurately evaluate cardiotoxicity.
The characteristics of human iPS cell-derived cardiomyocytes were quantitatively analyzed by experiments centered on single cell function analysis over the four years. As a result, it was demonstrated by expression system models and in silico models that the inward-rectifying potassium channel current is significantly lower than adult ventricular muscle, which greatly contributes to the resting membrane potential and automaticity of differentiated myocardium. Analysis of the beating video imaging of differentiated cardiomyocytes revealed differences in contractility and drug response depending on the expression pattern of contraction-related molecules. It can be expected that the cell motion analysis makes it possible to select more appropriate cells to evaluate certain drugs.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、突然死に代表される重篤な医薬品副作用の予防を長期的目標としている。今回の成果は、ヒトiPS細胞とコンピューターシミュレーションを統合することにより、評価結果のばらつきを生じさせる分子をあぶり出し、薬物による不整脈発生機構のメカニズムにつながる点が学術的に意義深い。
開発中の新薬が心臓に異常をもたらす心毒性は、上市後の創薬開発失敗の約3割を占める。大きな要因として、心筋はヒト培養細胞がなかったため、非臨床試験におけるリスク予測が困難であったことが挙げられる。今回、ヒトiPS細胞とシミュレーションを統合することで、非臨床安全性私見のリスク予測性が向上することが期待できる。
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Report
(5 results)
Research Products
(114 results)
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[Journal Article] Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction2018
Author(s)
Miyamoto K, Akiyama M, Tamura F, Isomi M, Yamakawa H, Sadahiro T, Muraoka N, Kojima H, Haginiwa S, Kurotsu S, Tani H, Wang L, Qian L, Inoue M, Ide Y, Kurokawa J, Yamamoto T, Seki T, Aeba R, Yamagishi H, Fukuda K, Ieda M.
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Journal Title
Cell Stem Cell
Volume: 4
Pages: 91-103
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Overexpression of KCNJ2 in induced pluripotent stem cell-derived cardiomyocytes for the assessment of QT-prolonging drugs2018
Author(s)
Li, M., Kanda, Y., Ashihara, T., Sasano, T., Nakai, Y., Kodama, M., Hayashi, E., Sekino, Y., Furukawa, T., and Kurokawa, J.
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Journal Title
J. Pharmacol. Sci.
Volume: 134
Pages: 75-85
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Efficient Large-Scale 2D Culture System for Human Induced Pluripotent Stem Cells and Differentiated Cardiomyocytes.2017
Author(s)
Toyama S, Fujita J*, Fujita C, Yamaguchi M, Kanaami S, Ohno R, Sakamoto K, Kodama M, Kurokawa J, Kanazawa H, Seki T, Kishino Y, Okada M, Nakajima K, Tanosaki S, Someya S, Hirano A, Kawaguchi S, Kobayashi E, Fukuda K
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Journal Title
Stem Cell Reports.
Volume: 9
Pages: 1406-1414
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] A multiscale computational modeling approach predicts mechanisms of female sex risk in the setting of arousal-induced arrhythmias2017
Author(s)
Yang PC, Perissinotti L, Lopez-Redondo F, Wang Y, DeMarco KR, Jeng MT, Vorobyov I, Harvey RD, Kurokawa J, Noskov S, Clancy CE
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Journal Title
J Physiol (Lond.)
Volume: 595
Pages: 4695-4723
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] A multiscale computational modeling approach predicts mechanisms of female sex risk in the setting of arousal-induced arrhythmias.2017
Author(s)
Yang PC, Perissinotti L, Lopez-Redondo F, Wang Y, DeMarco KR, Jeng MT, Vorobyov I, Harvey RD, Kurokawa J, Noskov S, Clancy CE
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Journal Title
J Physiol (Lond.)
Volume: 印刷中
Related Report
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Sall1 transiently marks undifferentiated heart precursors and regulates their fate.2016
Author(s)
Yuika Morita,Peter Andersen,Akitsu Hotta,Yuko Tsukahara,Noriko Sasagawa,Naoko Hayashida,Chizuko Koga,Misato Nishikawa,Yumiko Saga,Sylvia M. Evans, Kazuko Koshiba-Takeuchi,Ryuichi Nishinakamura,Yoshinori Yoshida,Chulan Kwon,Jun K. Takeuchi
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Journal Title
J Mol Cell Cardiol.
Volume: 192
Pages: 158-162
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A12016
Author(s)
Nagamori S, Wiriyasermkul P, Guarch ME, Okuyama H, Nakagomi S, Tadagaki K, Nishinaka Y, Bodoy S, Takafuji K, Okuda S, Kurokawa J, Ohgaki R, Nunes V, Palacín M, Kanai Y.
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Journal Title
Proc Natl Acad Sci U S A
Volume: 113
Pages: 775-780
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Enhancement of spontaneous activity by HCN4 overexpression in mouse embryonic stem cell-derived cardiomyocytes – A possible biological pacemaker2015
Author(s)
SaitoY, Nakamura K, Yoshida M, Sugiyama H, Ohe T, Kurokawa J, Furukawa T, Takano M, Nagase S, Morita H, Kusano KF, Ito H.
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Journal Title
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters2015
Author(s)
Kurokawa, J., Sasano, T., Kodama, M., Li, M., Ebana, Y., Harada, N., Honda, S.-I., Nakaya, H., & Furukawa, T.
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Journal Title
J. Toxicol. Sci.
Volume: 40
Issue: 3
Pages: 339-348
DOI
NAID
ISSN
0388-1350, 1880-3989
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Presentation] Study of long QT syndrome type 3 using human iPS-derived cardiomyocytes.2015
Author(s)
Furukawa T, Okata S, Yuasa S, Suzuki T, N Makita, J Kurokawa, T Egashira, H Yamanaka, T Seki, Y Aizawa, H Hashimoto, Y Kuroda, A Tanaka, K Yae, M Murata, T Aiba, W Shimizu, M Horie, K Kamiya, K Fukuda
Organizer
The 32nd Annual Scientific Meeting of the Japanese Society of Electrocardiology
Place of Presentation
京都，京都国際会館
Year and Date
2015-07-28
Related Report
Int'l Joint Research / Invited
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