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Development and electrophysiological analysis of genetically engineered transgenic mice for Brugada syndrome.

Research Project

Project/Area Number 13670685
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionHOKKAIDO UNIVERSITY

Principal Investigator

NAOMASA Makita  Hokkaido University Graduate School of Medicine, Instructor, 大学院・医学研究科, 助手 (00312356)

Co-Investigator(Kenkyū-buntansha) ITSUO Kodama  Research Institute of Environmental Medicine, Nagoya University, Professor, 環境医学研究所, 教授 (30124720)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2002: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2001: ¥3,000,000 (Direct Cost: ¥3,000,000)
KeywordsBrugada syndrome / Transgenic mice / Ventricular fibrillation / Na channel / Mutations / 不整脈 / パッチクランプ / 光シグナルマッピング
Research Abstract

Transgenic mice expressing human cardiac Na channel α subunit gene (SCN5A) under the control of myosin heavy chain promoter were developed. Two trains with wild type (WT) SCN5A and a missense mutation T1620M identified in a Brugada syndrome, a subtype of idiopathic ventricular fibrillation. Neither WT nor T1620M mice showed sudden death or ST elevation in right precordial leads characteristic for Brugada syndrome. Na channel blocker Pilsicainide failed to induce ST elevation or ventricular arrhythmias in T1620M, however, programmed electrophysiological studies with double extra stimuli on the right ventricular free wall provoked polymorphic ventricular tachycardia in T1620M but not in WT, suggesting the existence of arrhythmic substrates in the T1620M mice. Since the heart rate and the action potential configuration of mice are far from similar to those of human, further technological improvements such as developing bicistronic Na channel constructs expressing SCN5A and tag proteins or engineering knock-in animals, which in turn providing more suitable model animal to study the pathophysilogical mechanisms underlying the life-threatening disease Brugacla syndrome.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (48 results)

All Other

All Publications (48 results)

  • [Publications] Yamada T et al.: "Cloning of a functional splice variant of L-type calcium channel β_2 subunit from rat heart"J Biol Chem. 276. 47163-47170 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 蒔田直昌: "Brugada症候群とNaチャネル異常"呼吸と循環. 49. 421-428 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 蒔田直昌: "学会印象記:2000年Cardiac Electrophysiology Society Meetingに参加して"心電図. 21. 212-214 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 横井久卓: "不整脈の遺伝的要因"からだの科学. 221. 51-54 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 横井久卓: "遺伝子変異による不整脈"Medical Practice. 18. 278-279 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Makita N et al.: "Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation"Circulation. 106. 1269-1274 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 蒔田直昌: "Brugada症候群の成因"分子心血管病. 3. 73-77 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirai N et al.: "A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease"Cardiovasc Res. 53. 348-354 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 蒔田直昌: "心筋Na^+チャネル病の分子基盤"心臓. 34. 172-181 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ahmmed GU et al.: "Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes : Atrio-ventricular difference of moricizine block"Vascular Pharmacol. 38. 131-141 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yasuhashi T et al.: "L-cysteine prevents oxidation-induced block of the cardiac Na^+ channel via interaction with heart-specific cysteinyl residues in the P-loop region"Circ J. 66. 846-850 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 蒔田直昌: "心筋Na^+チャネル病の分子基盤"医学の歩み. 9. 661-665 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sugiura Y: "Cold induces shifts of voltage-dependence in a mutant SCN4A causing hypokalemic periodic paralysis"Neurology. (In press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 蒔田直昌: "遺伝子異常による不整脈の現況"診断と治療. (印刷中). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 中村一博: "アトルバスタチンは高脂血症患者の心-上腕動脈脈波伝播速度を改善する"心臓. (印刷中). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 佐々木孝治: "メディカルトピックスシリーズ 不整脈学2001"メディカルレビュー社. 205 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamada T et al.: "Cloning of a functional splice variant of L-type calcium channel β2 subunit from rat heart"J Biol Chem. 276. 47163-47170 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Makita N. et al.: "Brugada syndrome and Na channel mutations"Koku To Junkan. 49. 421-428 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Makita N et al.: "Overview of the Cardiac Electrophysiological Society Meeting 2000"Shindenzu. 21. 212-214 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yokoi H. et al.: "Genetic basis of arrhythmias"Karada No Kagaku. 221. 51-54 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yokoi H. et al.: "Genetic aspects of arrhythmias"Medical Practice. 18. 278-279 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Makita N et al.: "Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation"Circulation. 106. 1269-1274 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Makita et al.: "Pathophysiology of Brugada syndrome"Bunshi Kekkan Byo. 3. 73-77 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirai N et al.: "A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease"Cardiovasc Res. 53. 348-354 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Makita et al.: "Molecular basis of cardiac Na channelopathies"Shinzou. 34. 172-181 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ahmmed GU et al.: "Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes : Atrio-ventricular difference of moricizine block"Vascl Phramacol. 38. 131-141 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yasuhashi T et al.: "L-cysteine prevents oxidation-induced block of the cardiac Na^+ channel via interaction with heart-specific cysteinyl residues in the P-loop region"Circ J. 66. 846-850 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Makita et al.: "Molecular basis of cardiac Na channelopathies"Igaku No Ayumi. 9. 661-665 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sugiura Y et al.: "Cold induces shifts of voltage-dependence in a mutant SCN4A causing hypokalemic periodic paralysis"Neurology. (in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Makita et al.: "Genetic basis of Arrhythmias"Shindan To Chiryou. (in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakamura K et al.: "Atorvastatin improves arterial pulse wave velocity in patients with hypercholesterolemia"Shinzou. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sasaki K et al.: "Medical topics series"Arrhythmia 2001. (Review). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 蒔田直昌: "学会印象記:2000年Cardiac Electrophysiology Society Meetingに参加して"心電図. 21. 212-214 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] 横井久卓: "不整脈の遺伝的要因"からだの科学. 221. 51-54 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] 蒔田直昌: "イオンチャネルと不整脈"現代医療. 31. 988-994 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Naomasa Makita et al.: "Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation"Circulation. 106. 1269-1274 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ahmmed GU et al.: "Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes : Atrio-ventricular difference of moricizine block"Vascular Pharmacol. 38. 131-141 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yasuhashi T et al.: "L-cysteine prevents oxidation-induced block of the cardiac Na^+ channel via interaction with heart-specific cysteinyl residues in the P-loop region"Circ J. 66. 846-850 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 蒔田直昌: "心筋Na^+チャネル病の分子基盤"医学の歩み. 9. 661-665 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 蒔田直昌: "遺伝子異常による不整脈の現況"診断と治療. (印刷中). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 中村一博: "アトルバスタチンは高脂血症患者の心-上腕動脈脈波伝播速度を改善する"心臓. (印刷中). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 佐々木孝治: "メディカルトピックスシリーズ 不整脈学2001"メディカルレビュー社. 205 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamada T. ら: "Cloning of functional splice variant L-type calcium β_2 subunit from rat heart"J. Biol. Chem.. 276. 47163-47170 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shirai N. ら: "A mutant cardiac sodium channel with multiple biological defects ・・・"Cardiovascular Res.. 53. 348-354 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 横井 久卓ら: "遺伝子変異による不整脈"Medical Practice. 18. 278-279 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 蒔田 直昌: "Brugada症候群とNaチャネル異常"呼吸と循環. 49. 421-428 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 蒔田 直昌: "Brugada症候群の成因"分子心血管病. 3. 73-77 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 蒔田 直昌: "心筋Na^+チャネル病の分子病態"心臓. 34. 172-181 (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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