Mathematical analysis of arrhythmogenesis for bradycardia
| Project/Area Number |
17H04018
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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 physiology
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| Research Institution | Osaka University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
稲野辺 厚 大阪大学, 医学系研究科, 准教授 (00270851)
津元 国親 金沢医科大学, 医学部, 准教授 (70353331)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2019: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2017: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
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| Keywords | 心臓徐脈 / 心臓不整脈 / 心臓電気生理 / 数理解析 / 生理学 / シグナル伝達 |
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| Outline of Final Research Achievements |
G protein-gated inwardly rectifying K+ (KG) channel is a model effector for studying the signaling through GPCRs, G proteins and their effectors. Previously we have developed mathematical models for the bradycardia by combining the models representing molecular interactions and electrical activity of myocytes. While atypical KG channel activity was reported in patients with some supraventricular arrhythmias, previous models has a limitation to reproduce the pathological conditions without any hypotheses. In this study, we planned to uncover physiological modulators of KG channel function. We identified acridine derivatives which blocked KG channels in multiple modes of binding. They would assist to classify the activity of Kir channel members in living cells. We also found an endogenous blocker which binds at a crevasse of cytoplasmic domain of a KG channel subunit member Kir3.2. This novel drug-channel interaction was expected to be involved in physiological regulation.
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| Academic Significance and Societal Importance of the Research Achievements |
副交感神経の活動が活発になると、心臓ではKGチャネルが活性化し、心臓の拍動は緩やかになります。我々はチャネルの活性制御と心臓の拍動を共役させる統合的数理モデルを開発してきました。しかし、そのモデルでは心臓不整脈のチャネルの活動を再現出来ないため、拡張性の高い数理モデルの構築には新たなチャネル活性調節機構を想定する必要がありました。本研究では、チャネルを阻害する新規の薬物を同定すると共に、情報科学的に内因性の低分子が新規薬物結合部位に結合し、チャネル活性を阻害することを見出しました。以上の知見は、既存のモデルの改善と拡張性の高いモデルの構築の手掛かりになることが期待されます。
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Report
(4 results)
Research Products
(14 results)
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[Journal Article] Integrative and theoretical research on the architecture of a biological system and its disorder2019
Author(s)
Shinichi Uchida, Yoshiyuki Asai, Yoshiaki Kariya, Kunichika Tsumoto, Hiroshi Hibino, Masashi Honma, Takeshi Abe, Fumiaki Nin, Yasutaka Kurata, Kazuharu Furutani, Hiroshi Suzuki, Hiroaki Kitano, Ryuji Inoue, Yoshihisa Kurachi
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Journal Title
The Journal of Physiological Sciences
Volume: 69
Issue: 3
Pages: 443-451
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Systematic Expression Analysis of Genes Related to Generation of Action Potentials in Human iPS Cell-Derived Cardiomyocytes2019
Author(s)
Masami Kodama, Kazuharu Furutani, Reiko Kimura, Tomoko Ando, Kazuho Sakamoto, Shushi Nagamori, Takashi Ashihara, Yoshihisa Kurachi, Yuko Sekino, Tetsushi Furukawa, Yasunari Kanda, Junko Kurokawa
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Journal Title
Journal of Pharmacological Sciences
Volume: 140
Issue: 4
Pages: 325-330
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation.2019
Author(s)
Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
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Journal Title
Circulation
Volume: In press
Issue: 18
Pages: 2157-2169
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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