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Molecular Pathogenesis of Cardiac Failure due to Gene Abnormalities

Research Project

Project/Area Number 13470142
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionTokyo Medical and Dental University

Principal Investigator

KIMURA Akinori  Medical Research Institute, Dept. Molecular Pathogenesis, Professor, 難治疾患研究所, 教授 (60161551)

Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥9,800,000 (Direct Cost: ¥9,800,000)
Fiscal Year 2003: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2002: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥3,100,000 (Direct Cost: ¥3,100,000)
KeywordsGene / Cardiac Failure / Cardimyopathy / Stretch Response / Z-disk / Hypertension / Polymorphism / Mutation / 肥大型心筋症 / 拡張型心筋症 / Cypher変異 / PKC / カルサルチン / Tcap / カベオリン / 遺伝子変異 / トランスジェニックマウス / タイチン / MLP / ミオシン脱リン酸化 / 心肥大 / テレトニン
Research Abstract

Idiopathic cardiomyopathy was defined as cardiomyopathy of unknown etiology. Recent molecular genetic analysis has revealed that gene abnormalities are involved in the etiology and/or pathogenesis of idiopathic cardiomyopathy. As well, hypertensive cardiomyopathy may also be relevant to the gene abnormalities in the pathogenesis. In this study, we have revealed that mutations in the genes for Z-disk elements, TTN, TCAP, MLP, and Cypher, cause cardiomyopathy. Functional studies of the mutations in each disease gene have shown that hypertrophic cardiomyopathy-related mutations increase the binding ability of the Z-disk elements, whereas dilated cardiomyopathy-related mutations decrease the binding ability. It also has been demonstrated that the Z-disk plays a key role in the stretch-sensing of cardiomyocytes from the analysis of a well known dilated cardiomyopathy model of MLP deficient mice. It was suggested that the stretch-response involved phosphorylation of Z-disk proteins, because the Z-disk protein abnormalities were predicted to change the distribution of calcineurin and PKC. In addition, Ca-sensitization and -desensitization played a crucial role in the pathogenesis of cardiac hypertrophy and failure, respectively. Analysis of hypertrophied and dilated hearts from M21-transgenic mice and Dah1 salt-sensitive hypertensive rats by DNA-chip technology showed that a number of genes were involved in the pathogenesis of cardiomyopathy. One of the new genes identified to be differentially expressed in the cardiac hypertrophy and failure is a growth factor-like gene specifically expressed in the heart. We identified a mutation in that growth factor-like gene that was associated with hypertensive cardiomyopathy.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (32 results)

All Other

All Publications (32 results)

  • [Publications] Lee WH, Hwang TH, Kimura A, Park SW, Satoh M, Nishi H, Harada H, Toyama J.: "Different expressivity of a venticular essential light chain gene Ala57Gly mutation in familial hypertrophic cardiomyopathy."Am.Heart J.. 141. 184-189 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Arimura T, Suematsu N, Zhou YB, Nishimura J, Satoh S, Takeshita A.: "Identification, characterization and functional analysis of heart-specific myosin light chain pohsphatase small subunit."J.Biol.Chem.. 276. 6073-6082 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Soejima T, Kawamoto S, Akai J, Miyoshi O, Arai Y, Morohka T, Matsuo S, Niikawa N, Kimura A, Okubo K, Mukai T: "Isolation of novel heart-specific genes using the bodymap."Genomics. 74. 115-120 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kimura A, Itoh-Satoh M, Hayashi T, Takahashi M, Arimura T: "Molecular etiology of idiopathic cardiomyopathy in Asian populations."J Cardiol.. 37. S139-S146 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shirai N, Makita N, Sasaki K, Yokoi H, Sakuma I, Sakurada H, akai J, Kimura A, Hiraoka M, Kitabatake A: "Implication of an overlapping Na channelopathy in an idiopathic ventricular fibrillation associated witha a cardiac Na channel mutation."Cardiovasc Res.. 53. 348-354 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Itho-Satoh M, Hayashi T, Nishi H, Koga Y, Arimura T, Ueda K, Hohta S, Nouchi T, Takahashi M, Hiroe M, Marumo F, Imaizumi T, Yasunami M, Kimura A: "Titin mutations as the molecular basis for dilated cardiomyopathy."Biochem.Biophys.Res.Commun.. 291. 385-393 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Harada H, Kimura A, Fukino K, Yasunaga S, Nishi H, Emi M: "Genomic structure and eight exonic polymorphisms of the human N-cadherin gene."J Hum.Genet. 47. 330-332 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kuroda N, Ohnishi Y, Kimura A, Yokoyama A: "Clinical significance of T-wave alternans in hypertrophic cardiomyopathy"Circ.J.. 66. 457-462 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsumori A, Fukawa Y, Hasegawa K, Sato Y, Nakagawa H, MOrikawa Y, Miura K, Ohno Y, Inaba Y, Sasayama S, Fujiwara H, Hiroe M, Hori M, Imaizumi T, Inoko H, Izumi T, Kawai S, Kawana M, Kimura A, Kitabatake A, Kitamura S, Kitaura Y, Matsuzaki M, Nagai R, Ogawa S, Shimada T, Simotohno K, Takeda N, Takihara K, Tanaka M, Tei T, Toyo-oka T, Yamaguchi I, Yokoyama M, Yutani C: "Epidomiologic and clinical characteristics of cardiomyopathies in Japan : Analysis by nationwide surveys."Cir.J.. 66. 323-336 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Knoll R, Hoshijima M, Hoffmann HM, Person V, Lorenzen-Schmidt I, Bang M-L, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork J, Jeffrey H, Omens J, Andrew D, McCulloch A, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheless HP, Chien KR: "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy."Cell. 111. 943-955 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hayashi T, Arimura T, Ueda K, Shibata H, Hohda S, Takahashi M, Hori H, Koga Y, Oka N, Imaizumi T, Yasunami M, Kimura A: "Identification and functional analysis of a caveolon-3 mutation associated with familial hyoertrophic cardiomyopathy."Biochem.Biophys.Res.Commun. 313. 178-184 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Arimura T, Hayashi T, Terada H, Lee SY, Zhou Q, Takahashi T, Ueda K, Nouchi T, Hohda S, Sibutani M, Hirose M, Chen J, Park JE, Yasunami M, Hayashi H, Kimura A: "A Cyher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C"J.Biol.Chem.. 279. 6746-6752 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ogimoto A, Hamada M, Nakaura J, Shigematsu Y, Hara Y, Ohtsuka T, Morishima A, Kimura A, Miki T, Hiwada K: "17-year-old follow-up study of a patient with obstructive hypertrophic cardiomyopathy with a deletion mutation in the cardiac myosin binding protein C gene."Circ J. 68. 174-177 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Komamura K, Iwai N, Kokame K, Yasumura Y, Kim J, Yamagishi M, Morisaki T, Kimura A, Tomoike H, Kitakaze M, Miyatake K: "The role of a common TNNT2 polymorphism in cardiac hypertrophy."J.Hum.Genet.. 49. 129-133 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kimura A, Hayashi T, Itoh-Satoh M, Arimura T, Lee WH, Lee SY, Park JE: "Cardiomyopathies and Heart Failure : Biomolecular, Infections and Immune Mechanisms"Klumer Academic Publishers. 415-428 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kimura A, Itoh-Satoh M, Hayashi T, Takahashi M, Arimura T, Yaunami M, Lee SY, Hwang TH, Lee WH, Park JE: "Frontiers in Cardiovascular Health"Klumer Academic Publishers. 196-206 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Aizawa Y, et al.: "A novel mutation in FKBP12.6 binding region of the human cardiacryanodine receptor gene (R2401H) in Japanese patient with catecholaminergic polymorphic ventricular tachycadia."Int J Cardiol. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Hayashi T, et al.: "Identification and functional analysis of a caveolon-3 mutation associated with familial hypertrophic cardiomyopathy."Biochem.Biophys.Res.Commun. 313. 178-184 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Arimura T, et al.: "A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C."J.Biol.Chem.. 279. 6746-6752 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ogimoto A, et al.: "17-year follow-up study of a patient with obstructive hypertrophic cardiomyopathy with a deletion mutation in the cardiac myosin binding protein C gene."Circ J.. 68. 174-177 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kimura A, et al.: "In Cardiomyopathies and Heart Failure ; Biomolecular, Infectious and Immune Mechanisms (ed. Matsumori A)"klumer Academic Publishers, Boston. 415-428 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kimura A, et al.: "In Frontiers in Cardiovascular Health (eds. Dhalla NS, Chockalingam A, Berkovitz HI, Singal PK)"Klumer Academic Publishers, Boston. 195-206 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shirai N, et al.: "Implication of an overlapping Na channelopathy in an idiopathic ventricular fibrillation associated with a cardiac Na channel mutation"Cardiovase Res.. 53. 348-354 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Itoh-Satoh M, et al.: "Titin mutations as the molecular basis for dilated cardionayopathy"Biochem. Biophys. Res. Commun. 291. 385-393 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Knoell R, et al.: "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy"Cell. 111. 943-955

    • Related Report
      2002 Annual Research Report
  • [Publications] Kimura A, et al.: "Proceedings of ICCHF (eds. Matsumori A, et al.)"Klumer Academic Publishers, Boston(印刷中).

    • Related Report
      2002 Annual Research Report
  • [Publications] Kimura A, et al.: "Frontiers in Cardiovascular Health (eds. Dhalla NS, et al.)"Klumer Academic Publishers, Boston(印刷中).

    • Related Report
      2002 Annual Research Report
  • [Publications] Arimura T, Suematsu N, Zhou YB, et al.: "Identification, characterization and functional analysis of heart-specific myosin light chain phoshatase small subunit"J. Biol. Chem.. 276. 6073-6082 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Soejima T, Kawamoto S, Akai J, et al.: "Isolation of novel heart-specific genes using the bodymap"Genomics. 74. 115-120 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kimura A, Itoh-Satoh M, Hayashi T, et al.: "Molecular etiology of idiopathic cardiomyopathy in Asian populations"J Cardiol.. 37. S139-S146 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shirai N, Makita N, Sasaki K, et al.: "Implication of an overlapping Na channelopathy in an idiopathic ventricular fibrillation associated with a cardiac Na channel mutation"Cardiovasc Res.. 53. 348-354 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 1toh-Satoh M, Hayashi T, Nishi H, et al.: "Titin mutations as the molecular basis for dilated cardiomyopathy"Biochem. Biophys. Res. Commun.. 291. 385-393 (2002)

    • Related Report
      2001 Annual Research Report

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

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