Mathematical analysis of arrhythmogenesis for bradycardia

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H04018
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General physiology
• Research Institution: Osaka University
• Principal Investigator: Kurachi Yoshihisa 大阪大学, 国際医工情報センター, 教授 (30142011)
• 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)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 心臓徐脈

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.

Free Research Field

心臓生理学

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。