リアノジン受容体分子内特定ドメインをターゲットとした致死的不整脈の新しい治療

2008 Fiscal Year Annual Research Report

• Project/Area Number: 20590868
• Research Institution: Yamaguchi University
• Principal Investigator: 山本 健 Yamaguchi University, 大学院・医学系研究科, 助教 (50363122)
• Co-Investigator(Kenkyū-buntansha): 小林 茂樹 山口大学, 医学部附属病院, 助教 (90397993)
• Keywords: 心室性不整脈 / 興奮収縮連関

Research Abstract

リアノジン受容体分子内安定化機構を解明し、さらにアメリカ心臓協会(AHA)のCirculation誌において研究成果を論文として発表(Yamamoto T, Yano M, Xu X, Uchinoumi H, Tateishi H, Mochizuki M, Oda T, Kobayashi S, Ikemoto N, Matsuzaki M. Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. Circulation. 2008 Feb 12; 117(6): 762-772)した。またこの安定化ドメインの構造の詳細についてもBasic Cardiovascular Sciences Annual Conference 2009-Molecular MechanismsofCardiovascular Disease (2008/7 Keystone)にて発表を行った。さらにこのRyR分子内安定化機構をヒトCPVT型knock-in mouseに応用した結果CPVT型KI mouseのCa^<2+>sparkを抑制できることをアメリカ心臓協会(AHA)の2008年次集会(2008/11, Orlando, FL)において研究成果を発表(oral presentation)した。また日本循環器学会総会(2009/03,大阪)においても研究成果(poster & oral presentation)を発表した
研究は予定通り進行しリアノジン受容体の安定化に重要なドメインを同定できた。また同定した安定化ドメインが心不全のみならず致死的不整脈の治療にも有用であることがわかった。

Research Products

• [Journal Article] Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts. (2009)
  • Author(s): Tateishi H
  • Journal Title: Cardiovascular Research 81 Pages: 536-545
  • Peer Reviewed
• [Journal Article] Role of ryanodine receptor as a Ca(2+)regulatory center in normal and failing hearts. (2008)
  • Author(s): Yano M
  • Journal Title: J Cardiol 53 Pages: 1-7
  • Peer Reviewed
• [Journal Article] Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. (2008)
  • Author(s): Yamamoto T
  • Journal Title: Circulation 117 Pages: 762-72
  • Peer Reviewed
• [Presentation] Domain^<2114-2149> Within RyR2 Plays a Key Role for Correcting Channel Disorder in Catecholaminergic Polymorphic Ventricular Tachycardia(CPVT) (2008)
  • Author(s): Yamamoto T
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20081108-20081112
• [Presentation] Protein Phosphatase I Beta is Most Abundant Isoform in the Longitudinal Sarcoplasmic Reticulum and Regulates Phospholamban Phosphorylation in Cardiomyocytes (2008)
  • Author(s): Aoyama H
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20081108-20081112
• [Presentation] Mutation-Linked, Defective Inter-Domain Interaction within the Cardiac Ryanodine Receptor as a Critical Cause of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2008)
  • Author(s): Uchinoumi H
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20081108-20081112
• [Presentation] Decreased Affinity of Calmodulin Binding to RyR2 May Cause Leaky Channel in CPVT-Associated Mutation : Insight from RyR2 R2474s/+Knock-In Mouse Model (2008)
  • Author(s): Xu X
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20081108-20081112
• [Presentation] Abnormally Tight Domain-Domain Interaction at Mutation Site Could be a Primary Cause of Catecholaminergic Polymorphic Ventricular Tachycardia : Insight from RyR2^<S2246L/+> Knock-In Mouse Model (2008)
  • Author(s): Suetomi T
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20081108-20081112