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

• 研究課題/領域番号: 20590868
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 循環器内科学
• 研究機関: 山口大学
• 研究代表者: 山本 健 山口大学, 大学院・医学系研究科, 助教 (50363122)
• 研究分担者: 小林 茂樹 山口大学, 医学部附属病院, 助教 (90397993)
• 研究期間 (年度): 2008 – 2010
• 研究課題ステータス: 完了 (2010年度)
• 配分額: 4,550千円 (直接経費: 3,500千円、間接経費: 1,050千円); 2010年度: 1,040千円 (直接経費: 800千円、間接経費: 240千円); 2009年度: 1,300千円 (直接経費: 1,000千円、間接経費: 300千円); 2008年度: 2,210千円 (直接経費: 1,700千円、間接経費: 510千円)
• キーワード: 分子心臓病態学 / 致死的不整脈 / リアノジン受容体 / 興奮収縮連関 / 心不全 / 心室性不整脈

研究概要

リアノジン受容体の安定化に特に重要ドメインをdomain2114-2149とそのdomain-domain interactionのパートナーであることを特定した。パートナードメインはやはりセントラルドメインの中にあることも特定した。この2つのドメインに作用する薬物は心不全、致死的不整脈の治療薬になり得る。

研究成果

• [雑誌論文] Isoform-specific roles of protein phosphatase 1 catalytic subunits in sarcoplasmic reticulum-mediated Ca2+ cycling. (2011)
  • 著者名/発表者名: Aoyama H, Ikeda Y, Miyazaki Y, Yoshimura K, Nishino S, Yamamoto T, Yano M, Inui M, Aoki H, Matsuzaki M.
  • 雑誌名: Cardiovasc Res. 89(1) ページ: 79-88
  • 査読あり
• [雑誌論文] Urinary 8-Hydroxy-2' -Deoxyguanosine Reflects Symptomatic Status and Severity of Systolic Dysfunction in Patients with Chronic Heart Failure. (2011)
  • 著者名/発表者名: Kobayashi S, Susa T, Tanaka T, Wada Y, Okuda S, Doi M, Nao T, Yoshiga Y, Yamada J, Okamura T, Ueyama T, Kawamura S, Yano M, Matsuzaki M.
  • 雑誌名: Eur J Heart Fail. 13(1) ページ: 29-36
  • 査読あり
• [雑誌論文] Dantrolene, a therapeutic agent for malignant hyperthermia inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2 R2474S/+knock-in mouse model. (2010)
  • 著者名/発表者名: Kobayashi S, Yano M, Uchinoumi H, Suetomi T, Susa T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Yamamoto T, Matsuzaki M.
  • 雑誌名: Circ J. 74(12) ページ: 2579-2584
  • NAID: 10027424202
  • 査読あり
• [雑誌論文] Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure. (2010)
  • 著者名/発表者名: Ono M, Yano M, Hino A, Suetomi T, Xu X, Susa T, Uchinoumi H, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M.
  • 雑誌名: Cardiovasc Res. 87(4) ページ: 609-617
  • 査読あり
• [雑誌論文] Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction. (2010)
  • 著者名/発表者名: Xu X, Yano M, Uchinoumi H, Hino A, Suetomi T, Ono M, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, lkeda Y, lkemoto N, Matsuzaki M.
  • 雑誌名: Biochem Biophys Res Commun. 394(3) ページ: 660-666
  • 査読あり
• [雑誌論文] Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor. (2010)
  • 著者名/発表者名: Uchinoumi H, Yano M, Suetomi T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, lkeda Y, Ohkusa T, lkemoto N, Matsuzaki M.
  • 雑誌名: Circ Res. 106(8) ページ: 1413-1424
  • 査読あり
• [雑誌論文] Norepinephrine spillover during exercise as a novel parameter to evaluate the severity of heart failure. (2010)
  • 著者名/発表者名: Ando M, Yamamoto T, Hino A, Sato T, Nakamura Y, Matsuzaki M.
  • 雑誌名: J Nucl Cardiol. 17(5) ページ: 868-873
  • 査読あり
• [雑誌論文] Norepinephrine spillover during exercise as a novel parameter to evaluate the severity of heart failure (2010)
  • 著者名/発表者名: Ando M
  • 雑誌名: J Nucl Cardiol 巻: 17 ページ: 868-873
  • 査読あり
• [雑誌論文] Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor. (2010)
  • 著者名/発表者名: Uchinoumi H
  • 雑誌名: Circ Res 巻: 106 ページ: 1413-1424
  • 査読あり
• [雑誌論文] Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure. (2010)
  • 著者名/発表者名: Ono M
  • 雑誌名: Cardiovasc Res 巻: 87 ページ: 609-617
  • 査読あり
• [雑誌論文] Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction. (2010)
  • 著者名/発表者名: Xu X
  • 雑誌名: Biochem Biophys Res Commun 393 ページ: 660-666
  • 査読あり
• [雑誌論文] Catecholaminergic Polymorphic Ventricular Tachycardia Is Caused by Mutation-Linked Defective Conformational Regulation of the Ryanodine Receptor. (2010)
  • 著者名/発表者名: Uchinoumi H
  • 雑誌名: Circ Res. 106 ページ: 1413-1424
  • 査読あり
• [雑誌論文] Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor. (2009)
  • 著者名/発表者名: Kobayashi S, Yano M, Suetomi T, Ono M, Tateishi H, Mochizuki M, Xu X, Uchinoumi H, Okuda S, Yamamoto T, Koseki N, Kyushiki H, lkemoto N, Matsuzaki M.
  • 雑誌名: J Am Coll Cardiol. 53(21) ページ: 1993-2005
  • 査読あり
• [雑誌論文] Role of ryanodine receptor as a Ca2+ regulatory center in normal and failing hearts. (2009)
  • 著者名/発表者名: Yano M, Yamamoto T, Kobayashi S, Matsuzaki M.
  • 雑誌名: J Cardiol. 53(1) ページ: 1-7
  • NAID: 10025182309
  • 査読あり
• [雑誌論文] Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts. (2009)
  • 著者名/発表者名: Tateishi H, Yano M, Mochizuki M, Suetomi T, Ono M, Xu X, Uchinoumi H, Okuda S, Oda T, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M.
  • 雑誌名: Cardiovasc Res. 81(3) ページ: 536-545
  • 査読あり
• [雑誌論文] Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Markedly Improves the Function of Failing Cardiomyocytes by Stabilizing Interdomain Interactions Within the Ryanodine Receptor (2009)
  • 著者名/発表者名: Kobayashi S
  • 雑誌名: Journal of the American College of Cardiology 53 ページ: 1993-2005
  • 査読あり
• [雑誌論文] Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts. (2009)
  • 著者名/発表者名: Tateishi H
  • 雑誌名: Cardiovascular Research 81 ページ: 536-545
  • 査読あり
• [雑誌論文] Defective Ca2+ cycling as a key pathogenic mechanism of heart failure. (2008)
  • 著者名/発表者名: Yano M, Yamamoto T, Kobayashi S, Ikeda Y, Matsuzaki M.
  • 雑誌名: Circ J. 72
  • NAID: 110006935628
  • 査読あり
• [雑誌論文] Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. (2008)
  • 著者名/発表者名: Yamamoto T, Yano M, Xu X, Uchinoumi H, Tateishi H, Mochizuki M, Oda T, Kobayashi S, Ikemoto N, Matsuzaki M.
  • 雑誌名: Circulation. 117(6) ページ: 762-772
  • 査読あり
• [雑誌論文] Role of ryanodine receptor as a Ca(2+)regulatory center in normal and failing hearts. (2008)
  • 著者名/発表者名: Yano M
  • 雑誌名: J Cardiol 53 ページ: 1-7
  • 査読あり
• [雑誌論文] Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. (2008)
  • 著者名/発表者名: Yamamoto T
  • 雑誌名: Circulation 117 ページ: 762-72
  • 査読あり
• [学会発表] Interruption of Novel Inter-domain Interaction Within RyR2 as a Common Therapeutic Target by Channel Stabilization in Heart Failure and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2010)
  • 著者名/発表者名: Takeshi Yamamoto, Masafumi Yano, Masahiro Fukuda, Akihiro Hino, Takeshi Suetomi, Masahiro Doi, Shinich Okuda, Shigeki Kobayashi, Masunori Matsuzaki
  • 学会等名: American Heart Association Scientific Sessions
  • 発表場所: Chicago IL, USA
  • 年月日: 2010-11-15
• [学会発表] Interruption of Novel Inter-domain Interaction Within RyR2 as a Common Therapeutic Target by Channel Stabilization in Heart Failure and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2010)
  • 著者名/発表者名: Takeshi Yamamoto
  • 学会等名: American Heart Association Scientific Sessions 2010
  • 発表場所: Chicago IL
  • 年月日: 2010-11-15
• [学会発表] Role of Domain(2114-2149) Within RyR2 for Channel Stabilization in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2009)
  • 著者名/発表者名: Yamamoto T
  • 学会等名: Basic Cardiovascular Sciences Annual Conference
  • 発表場所: Lake LasVegas, NV, USA
  • 年月日: 2009-07-27
• [学会発表] Domain2114-2149 Within RyR2 Plays a Key Role for Correcting Channel Disorder in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2008)
  • 著者名/発表者名: Yamamoto, T, Yano, M, Suedomi, T, Ohno, M, Xu, XJ, Tateishi, H, Okuda, S, Kobayashi, S, Ikeda, Y, Matsuzaki, M
  • 学会等名: Scientific Sessions 2008 of American Heart Association
  • 発表場所: NewOrleans, USA
• [学会発表] Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts (2008)
  • 著者名/発表者名: Yamamoto, T, Yano, M, Suedomi, T, Ohno, M, Xu, XJ, Tateishi, H, Okuda, S, Kobayashi, S, Ikeda, Y, Matsuzaki, M
  • 学会等名: Basic Cardiovascular Sciences Annual Conference 2009-Molecular Mechanisms of Cardiovascular Disease.
  • 発表場所: Keystone, USA
• [学会発表] Domain^<2114-2149> Within RyR2 Plays a Key Role for Correcting Channel Disorder in Catecholaminergic Polymorphic Ventricular Tachycardia(CPVT) (2008)
  • 著者名/発表者名: Yamamoto T
  • 学会等名: AHA Scientific Session
  • 発表場所: New Orleans, USA
• [学会発表] Protein Phosphatase I Beta is Most Abundant Isoform in the Longitudinal Sarcoplasmic Reticulum and Regulates Phospholamban Phosphorylation in Cardiomyocytes (2008)
  • 著者名/発表者名: Aoyama H
  • 学会等名: AHA Scientific Session
  • 発表場所: New Orleans, USA
• [学会発表] Mutation-Linked, Defective Inter-Domain Interaction within the Cardiac Ryanodine Receptor as a Critical Cause of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2008)
  • 著者名/発表者名: Uchinoumi H
  • 学会等名: AHA Scientific Session
  • 発表場所: New Orleans, USA
• [学会発表] Decreased Affinity of Calmodulin Binding to RyR2 May Cause Leaky Channel in CPVT-Associated Mutation : Insight from RyR2 R2474s/+Knock-In Mouse Model (2008)
  • 著者名/発表者名: Xu X
  • 学会等名: AHA Scientific Session
  • 発表場所: New Orleans, USA
• [学会発表] 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)
  • 著者名/発表者名: Suetomi T
  • 学会等名: AHA Scientific Session
  • 発表場所: New Orleans, USA
• [図書] Heart Failure Pathophyiology in upportive Care in Heart Failure. (2008)
  • 著者名/発表者名: Ikeda Y, Yamamoto T, Yano M, Matsuzaki M.
  • 出版者: Oxford University Press. Ch.
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