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心筋の分化、成長過程における細胞内カルシウム調節機構とその異常

Research Project

Project/Area Number 12136206
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionJikei University School of Medicine

Principal Investigator

須田 憲男  東京慈恵会医科大学, 医学部, 講師 (80201581)

Co-Investigator(Kenkyū-buntansha) 大野 哲生  東京慈恵会医科大学, 医学部, 助手 (30233224)
福田 紀男  東京慈恵会医科大学, 医学部, 助手 (30301534)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥55,400,000 (Direct Cost: ¥55,400,000)
Fiscal Year 2004: ¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2003: ¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2002: ¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2001: ¥13,900,000 (Direct Cost: ¥13,900,000)
Keywords再生医学 / シグナル伝達 / 発生・分化 / 循環器・高血圧 / 生理学 / 心不全 / 心筋 / カルシウム / 筋小胞体 / クロスブリッジ / 筋長効果 / スキンドファイバー / タイチン / トリプシン / アシドーシス / コネクチン / カルシウム放出 / リアノジン受容体
Research Abstract

1)心不全発症遺伝子改変マウスに関する研究:PDK1 KOマウス心筋の機能解析:PDKlはホスホイノシトイド3-リン酸の重要なエフェクターであるリン酸化酵素であるが、この酵素を欠損する遺伝子改変マウスは出生後5-6週で心不全を発症し死亡する。PDK1 KOマウス全心臓を用いて、心不全の病態に密接に関連するβ受容体の刺激応答性について検討したところ、β受容体刺激薬のイソプロテレノール(ISO)による陽性変力作用がみられなかった。アデニレートシクラーゼを活性化するホルスコリンによっても陽性変力作用はみられず、各種プロテインフォスファターゼ(PP)のうち、心筋L型Ca^<2+>チャネル(CACNA1C)の脱リン酸化を抑制するとされるPP2A阻害剤のCalyculin A存在下でのみISOによる陽性変力作用がみられた。従って、PDK1 KOマウスではCa^<2+>チャネルのリン酸化が強く抑制されている可能性が示唆された。2)2次性副甲状腺機能亢進症(SHPTH)患者の副甲状腺細胞に発現するCACNAICに関する研究:長期透析患者でSHPTHを発症する者は高頻度に心肥大や心不全を発症する。高PTH値を呈する透析患者を対象に遺伝子統計解析を適用した結果、CACNAICが関連遺伝子として示唆された。そこで、我々はSHPTH患者より得られた培養副甲状腺細胞に、免疫染色、細胞内Ca^<2+>測定、および電気生理学的測定を適用し、CACNAICがCa^<2+>流入経路として機能し得ることを証明した。3)Ca^<2+>増幅効率に関する研究:Ca2+低親和性蛍光色素であるFluo-5Nをウサギの単一心室筋細胞に負荷したところ、筋小胞体Ca^<2+>放出に伴う蛍光強度の減少が確認された。4)筋原線維の水の束縛力に関する研究:筋原線維懸濁液の水プロトンNMR信号の緩和時定数の解析により、筋原線維は、静電作用で考えられる距離の1000倍ほど遠くの水まで束縛し、線維の周りに厚い水和層を形成していることが示唆された。

Report

(5 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (29 results)

All 2005 2004 Other

All Journal Article (12 results) Publications (17 results)

  • [Journal Article] Reduced beta-adrenergic response in mouse hearts lacking PDK12005

    • Author(s)
      Matsuba D, Takemori S, Suda N et al.
    • Journal Title

      Biophysical Journal 88

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Parathyroide cells in patients with secondary hyperparathyroidism express functional alpha 1C subunit of L-type calcium channel2005

    • Author(s)
      Yokoyama K, Suda N et al.
    • Journal Title

      Biophysical Journal 88

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Inhibition of calcium-induced calcium release by tetanic stimulation in skeletal myotubes2005

    • Author(s)
      Matsuba D, Suda N
    • Journal Title

      Biophysical Journal 88

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Parathyroid cells express functional alpha 1C subunit of L-type calcium channel (CACNA1C)2005

    • Author(s)
      Matsuba D, Suzuki A, Suda N et al.
    • Journal Title

      Journal of Pharmacological Science 97,suppl1

      Pages: 92-92

    • NAID

      130005447810

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Reduced beta adrenergic response in the mouse whole hearts lacking PDK12005

    • Author(s)
      Suda N, Matsuba D, et al.
    • Journal Title

      Journal of Pharmacological Science 97,suppl1

      Pages: 180-180

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Parathyroid cells express functional alpha 1C subunit of L-type calcium channel (CACNA1C)2005

    • Author(s)
      Matsuba D, Suda N et al.
    • Journal Title

      Jpn.J.Physiol. (in press)

    • NAID

      130005447810

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Dihydropyridine-sensitive calcium entry activated by physiological increase in extracellular calcium concentration in human yperparathyroid cells.2005

    • Author(s)
      Suzuki A, Suda N et al.
    • Journal Title

      Jpn.J.Physiol. (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Could phosphorylated Tropoinin I by beta-adrenergic stimulation be dephosphyrylated simply by removal of the drug?2005

    • Author(s)
      Suda N, Matsuba D, Takemori S
    • Journal Title

      Jpn.J.Physiol. (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Parathyroid cells in patients with secondary hyperparathyroidism show functional voltage-gated calcium channel activity2005

    • Author(s)
      Yokoyama K, Suda N, et al.
    • Journal Title

      The Jpn.J.Nephrology 47(3)(in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Pharmacological properties of voltage calcium channels expressed in hyperparathyroid cells2005

    • Author(s)
      IidaR, Suda N et al.
    • Journal Title

      The Jpn.J.Nephrology 47(3)(in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Contractile properties of young mouse cardiac myocytes2004

    • Author(s)
      Suda N, Matsuba D
    • Journal Title

      Jpn.J.Physiol. 54

    • NAID

      130007039396

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 筋原線維の束縛力2004

    • Author(s)
      木村雅子, 大野哲生 他
    • Journal Title

      生物物理 44

    • Related Report
      2004 Annual Research Report
  • [Publications] Suda N: "A molecular mechanism underlying swift relaxation of tetanized muscles"Jpn J Physiol. 53. S194 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Suda N, Matsuba D: "Contractile properties of young mouse cardiac myocytes"Jpn J Physiol. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 千葉 允文, 竹森 重, 大野 哲生, 山口 眞紀: "筋原線維近傍の水には、遠達する束縛力が及んでいる"生物物理. 43. S130 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kusakari Y: "Fundamental properties of the relaxation between cytosolic Ca and isometric tension in mouse ventricular muscles-comparison with ferret and rat"J.Muscle Res Cell Motil. 23. 181 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suda N: "A molecular mechanism underlying swift relaxation of tetanized muscles"Jpn J Physiol. (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fukuda N: "Length dependence of tension generation in rat skinned cardiac muscle : role of titin in the Frank-Starling mechanism of the heart"Circulation. 104巻. 1639-1645 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukuda N: "Acidosis or inorganic phosphate enhances the length dependence of tension in rat skinned cardiac muscle"J Physiol.. 536巻. 153-160 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukuda N: "Regulation of Ca sensitivity of contractile elements in cardiac muscle. Clinical calcium"Clinical calcium. 11巻. 707-712 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukuda N: "Effect of acidosis on length-dependent activation in skinned cardiac muscle"Jpn. J. Physiol.. 51巻. S162 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamaguchi M: "Studies of the water state in the frog skeletal muscle"Jpn. J. Physiol.. 51巻. S168 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sasaki D: "Relationship between myocardiac spoc and heartbeat"Biophys. J.. 82巻. 600a (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Suda N: "Repolarization Inhibits caffeine-Induced Ca^<2+> release In skeletal myotubes."Journal of Muscle Research Cell Motility. 21巻. 193 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Suda N: "Low serum promotes maturation of excitation-contraction coupling in myotubes."Pfluegers Archiv. 439巻. 555-558 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Lorenzon N: "N-terminal tagging of the skeletal ryanodine receptor with green fluorescent protein does not interfere with the restoration of bi-directional coupling."Archives of Biochemistry and Biophysics.. (発表予定). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kajiwara H: "Effect of troponin I phosphorylation by protein kinase A on length-dependence of tension activation in skinned cardiac muscle fibers."Biochem Biophys Res Commun.. 272巻. 104-110 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Fukuda N: "Effect of acidosis on length dependence of tension generation in skinned cardiac muscle."Biophysical Journal. 80巻. 259a (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 福田紀男: "心筋の長さ-張力関係のメカニズム"生物物理. 40巻. S61 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2001-04-01   Modified: 2018-03-28  

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