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心筋細胞分化の制御とその異常

Research Project

Project/Area Number 06274102
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Research InstitutionThe University of Tokyo

Principal Investigator

矢崎 義雄  東京大学, 医学部附属病院, 教授 (20101090)

Co-Investigator(Kenkyū-buntansha) 松尾 寿之  国立循環器病センター研究所, 所長 (50028685)
中尾 一和  京都大学, 医学部, 教授 (00172263)
篠山 重威 (篠山 茂威)  京都大学, 医学部, 教授 (70109007)
古賀 義則  久留米大学, 医学部, 助教授 (50080669)
多田 道彦  大阪大学, 医学部, 教授 (90093434)
Project Period (FY) 1994 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥140,000,000 (Direct Cost: ¥140,000,000)
Fiscal Year 1997: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1996: ¥16,100,000 (Direct Cost: ¥16,100,000)
Fiscal Year 1995: ¥55,400,000 (Direct Cost: ¥55,400,000)
Fiscal Year 1994: ¥65,500,000 (Direct Cost: ¥65,500,000)
Keywordshomeobox / cardiomyophothy / ryanodinereceptor / atrialnatriuretic peptide / endothelin / adrenomedulin / long QT syndrome / ryanodinerecepter / adrenomedvlin / ホメオボックス / エンドセリン / gpl30 / カルシウム遊離チャンネル / 心不全 / 心肥大 / ANP / BNP / gp130
Research Abstract

心筋特異的ホメオボックス遺伝子CSXの解析の結果、CSXは心筋に存在する未知の蛋白質により発現調節をうけること、CSXは心房性ナトリム利尿ペプチド、脳型クレアチンキナーゼなど心臓に発現する遺伝子の転写を調節すること、さらにその際GATA4など心臓に発現している他の転写因子と協調して働くことなどが明らかになった。またエンドセリン-1の遺伝子欠損マウスは頭頚部の鰓弓由来組織、器官、大動脈の異常や心室中陥欠損を示した。このマウスにおいてbHLH型転写因子であるHANDの発現が低下していた。
心臓疾患においてもその異常が遺伝子変異によっておこることが明らかとなってきた。その代表が肥大型心筋症におけるサルコメアを構成する遺伝子の異常であり、QT延長症候群におけるイオンチャネル遺伝子の異常である。当研究班により日本における肥大型心筋症の遺伝子異常を解析したところ、β型ミオシン重鎖、トロポニンT、トロポミオシン、ミオシン結合蛋白Cの遺伝子に点変異をもつ肥大型心筋症の患者が存在した。またミオシン重鎖点変異の内、電位の変化をおこすものでは予後が悪いこと、さらに心筋病変の程度はトロポニンT、βミオシン重鎖、ミオシン結合蛋白Cの順に高度であり、トロポニンT変異例は心肥大の程度は軽いが、拡張相に移行する傾向があった。ミオシンの変異により心筋症のおこる機序について明らかにするために、粘菌を用いて変異ミオシンを作成し、in vitro motility assayによりアクチンの滑り速度を測定し、光ピンセット法により分子レベルで力を測定した。ミシオンの変異により滑り速度は全て低下していたが、予後の悪い点変異では力レベルも低下していた。家族性QT延長症候群の遺伝子解析の結果、32家系において2つのカリウムチャネル(KVLQT1、HERG)に9つの新しい変異を発見した。遺伝性心筋症ハムスターは、ヒト心筋症の良いモデルとして古くから解析されていた。心筋症ハムスターの心筋では、細胞骨格系の蛋白質dystrophinとその結合蛋白質群との複合体が正常に形成されておらず、筋肉細胞特異的なα、β、γサルコグリカンが著しく減少していた。RLGS法を用いてシリアンハムスターの1cMマップを作成し、戻し交配家系を用いた連鎖解析により、心筋症原因遺伝子を同定した。心筋症ハムスターにおいてはδサルコグリカン遺伝子が大きく欠失しており、ハムスター心臓にはδサルコグリカンのmRNAは発現していなかった。以上のようにこの班研究により、心臓の発生分化から遺伝病の遺伝子異常まで、実に多くのことが明らかになり、心臓病の病態生理に関する理解は飛躍的に高まったといえよう。

Report

(4 results)
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • 1994 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Komuro.I., Yazaki Y.: "Intracellular Signaling Pathway in Cardiac Myocytes Induced by Mechanical Stress" Trends Cardiovasc Med. 4. 117-121 (1994)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamazaki T., Komuro I.et al: "Mechanical Stress Activates Protein Kinase cascade of Phosphorylation in Neonatal Rat Cardiac Myocytes" J.Clin Invest. 96. 438-446 (1995)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamazaki T., Komuro I.et al: "Angiotensin II Partly Mediates Mechanical Stress-Induced Cardiac Hypertrophy" Circ Res. 77. 258-265 (1995)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamazaki T., Komuro I.et al: "Endothelin-1 is Involved in Mechanical Stress-induced Cardiomyocyte Hypertrophy" J.Biol Chem.271. 3221-3228 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Komuro I., Kudo S.et al: "Mechanical Stretch activates the stress-activated proteinkinases in Cardiac myocytes" FASEB J.10. 631-636 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Shiojima I., Komuro I.et al: "Molecular Cloning and Characterization of Human Cardiac Homeobox Gene CSX1" Circ Res. 79. 920-929 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Komuro I., Izumo S.: "Cardiac-specific homeobox-containing gene of the mause.in "Developmental mechanisms of heart disease"" Markwald R.R.,Clark E.B.Takao A.Futura N.Y., 679 (1955)

    • Related Report
      1997 Annual Research Report
  • [Publications] Komuro I., Shiojima I., Izumo S., Nagai R., Yazaki Y.: "Human and murine cardiac-specific homeobox-centaining genes.in "Cardiac Development and Gene Regulation"" Yazaki Y.Excerpta Medica,Ltd.Tokyo, 153 (1995)

    • Related Report
      1997 Annual Research Report
  • [Publications] Komuro I.,Kudo S.et al: "Mechanical stretch activates the stress-activated protein kinases in cardiac myocytes" FASEB J. 10(5). 631-636 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yamazaki T.,Komuro I.et at: "Endothelin-Is Involved in Mechanical stress-induced Cardiomyocyte Hypertrophy" J Biol Chem. 271(6). 3221-3228 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Sholjima I.,Komuro I.et al: "Molecular Cloning and Characteriaztion of Human Cardiac Homeobox Gene CSX1" Circ Res. 79(5). 920-929 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Zou Y.,Komuro I.et al: "Protein Kinase C,but Not Tyrosine Kinases or Ras,Plays a Critical Role in AngiotensinII induced Activation of Raf-1 Kinase and Extracellular Signalt Protein Kinases in Cardiac Myocytes" J Biol Chem. 271(52). 33592-33597 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yamazaki T.,Komuro I.et al: "Molecular aspects of mechanical stress-induced cardiac hypertrophy." Mol Cell Biochem. 163/164. 197-201 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kudoh S., Komuro I.et al: "Angiotensin II Stimulates C-Jun NH_2-Terminal Kinase in Cultured Cardiac Myocytes of Neonatal Rats" Circ Res. 80(1). 139-146 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Komuro I.,Izumo S.: "Cardiac-specific homeobox-containing gene of the mouse.in“Developmental mechanisms of heart disease"" Markwald RR.,Clark E.B.,Takao A.Futura N.Y, 697 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Komuro I.,Shiojima I.,Izumo S.et al: "Human and murine cardiac-specific homeobox-containing genes.in“Cardiac Development and Gene Regulation"" Yazaki Y.Excerpta Medica.Let.Tokyo, 153 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Otsu K,Nishida K,Kimura Y.et.al: "Evidence that the single amino acid ma tation,arg615 to cys in the Ca^<2+> release channel of skeletal sanoplasinic reticulum is of calignant hyperthenmia" J Biol Chem. 13. 1145-1154 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kamuro I,Schalling M,Jahn L.et.al.: "Gtx:Ancvel homecbox-crtairing geme,expressed specifically ingiial cells of the brain and germ cells of testis,acts asu nanscr.pticnal nepneser fora serim-inducible promoter" EMBOJ. 12(4). 1387-1401 (1993)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yamauchi-Takihara K,Ihara Y.et.al.: "Hypoxic Stressinduces curdiac myocyte-derived interlerkin-6." Circulation. 91. 1520-1524 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hirota H,Yoshida K,Kishimoto T.et.al.: "Continuousactivation of gp13o,a signol-transduing receptov conpenent for jnterleukin 6-reiated cytckines causes myocardial hypeitrophy in mice." Proc Natl Acad Sci USA. 92. 4862-4866 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kurihara Y,Kurihara H.etal.: "Elevaten blocd pressure and cranicfacial abnormalities in mice deficientin endothelin-l" Nature. 368. 703-710 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] Komuro I,Izumos,: "Cax:Amurine hameobox-containing gene specifcally expressed in the elevelping heart" Proc Natl Acad Sci USA. 90(17). 8145-8149 (1993)

    • Related Report
      1995 Annual Research Report
  • [Publications] Komuro I,Izumo S,: "Cardiac-specific homecbox-containing gene of the mouse,in “Developmental mechanisms of heart disease"" Markwald,RP,Clark,EB.Takao A,Futura,N.Y., 679 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Komuro I,Shiojima I.et.al: "Hyman and murine cardiac-specific homeobox-containing gene “Cardiac Developmemt and Gene Regulatior"" Yazaki Y,Excerpta Medica,Tokyo, 153 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] M.Kojima,Y.Yazaki et.al.: "Angiotensin II receptor antageniot TCV-116 induces regression of hypertensive left vertiuidar hypertrophy in vivo and inhibits the intracellular signaling pathway of strechmediated cardiomyocyte hypertrophy in vitro" Circulation. 89(5). 2204-2211 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Y.Kihara,S.Sasayama et.al.: "Sodium/calcium excharge moduiates intraceliur,calcium overload during pasthypoxic reoxaehation in manmaiirn worpiny myocardium" Journal of Clinical Invention. 93. 1275-1284 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Otsu K.Tada-M et.al.: "The point mutation Arg615--7Cys in the Ca^<2+> release channel of skeletal sarooplasmic reticulum is responsible for hypersensitivity to caffeine and halothane in malignant hyperthermia" J-Biol-chem.269(13). 9413-9415 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Sugo S.,Matsuo H.et.al.: "Production and secretion of adrenomedullin from vasoular smooth muscle cells augmented production by tumor necrosis factor alpha" Biochem-Biophys-Res-Commum. 203(1). 719-726 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ogawa Y.,Nakao K.et.al: "Molecular cloning of the complementary DNA and gene that encode.mouse brair natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene." J-Clin-Invent.93(5). 1911-1921 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Koga Y.et al.: "Therapeutic management of dilated cardiomyopathy" Cardiovasc-Drugs-Ther. 8(1). 83-88 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] I.Shiojima et.al.: "Diastolic Relaxation of the Heart" Kluwer Academic Publishers Boston, 348 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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