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難治性心疾患の病態発現における性差構築の分子機序

Publicly Offered Research

Project AreaMolecular mechanisms for establishment of sex differences.
Project/Area Number 23132507
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTokyo Medical and Dental University

Principal Investigator

木村 彰方  東京医科歯科大学, 難治疾患研究所, 教授 (60161551)

Project Period (FY) 2011-04-01 – 2013-03-31
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2012: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
Fiscal Year 2011: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
Keywords拡張型心筋症 / ラミンA/C / 遺伝子変異 / 性差 / 性ホルモン / アンドロゲンレセプター / SRF / 心筋リモデリング / 心不全 / テストステロン / 肥大型心筋症 / 動脈硬化 / マクロファージ
Outline of Annual Research Achievements

循環器系難治疾患の病態発現における性差の分子機構を解明することを目的とした。重症心不全を来し、現在のところ心臓移植しか根治療法がない拡張型心筋症は男性患者が多い(男女比2.6)ことおよび男性の方が重症であることが知られている。拡張型心筋症の20-30%は常染色体優性遺伝性疾患であるが、遺伝性であってもその病態には性差がある。拡張型心筋症の多発家系において、男性患者は30代~40代で発症し、生存予後が不良であるのに対し、女性患者は50代~60代で発症する明らかな性差を認めたが、この家系の病因変異としてラミンA/C遺伝子(LMNA)のR225X変異を特定した。一方、LMNA-H222P変異をノックインしたラミン変異マウスでは雄が早く発症し、雌よりも生存予後が不良であることを報告している。ラット心筋細胞にR225XもしくはH222P変異を持つLMNAを導入したところ、テストステロンの非存在下でもアンドロゲンレセプター(AR)が核内に集積することを見出した。また、この際に、FHL2およびSRFの核内集積も亢進していた。さらに、R225X変異を有する拡張型心筋症患者およびラミン変異マウスの心筋組織においても、AR、FHL2およびSRFの核内集積の亢進が確認された。ついで、ラミン変異マウスを用いて、性ホルモンによる拡張型心筋症の病態への影響を検討した。雄マウスは去勢やAR阻害剤よび投与によって病態が軽減するのに対し、雌マウスでは男性ホルモン投与で病態が悪化した。また、病態の変化は心筋の病理所見およびリモデリング関連遺伝子の発現変化によって確認された。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • Research Products

    (17 results)

All 2013 2012 2011

All Journal Article (10 results) (of which Peer Reviewed: 10 results) Presentation (7 results)

  • [Journal Article] Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue2013

    • Author(s)
      Crocini C, Arimura T, Reischmann S, Eder A, Braren I, Hansen A, Eschenhagen T, Kimura A, Carrier L
    • Journal Title

      Basic Res Cardiol

      Volume: (in press) Issue: 3 Pages: 349-349

    • DOI

      10.1007/s00395-013-0349-x

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations2013

    • Author(s)
      Arimura T, Onoue K, Takahashi-Tanaka Y, Ishikawa T, Kuwahara M, Setou M, Shigenbu S, Yamaguchi K, Bertrand AT, Machida N, Takayama K, Fukusato M, Tanaka R, Somekawa T, Nakano T, Yamane Y, Kuba K, Imai Y, Saito N, Bonne G, Kimura A
    • Journal Title

      Cardiovasc Res

      Volume: (in press) Issue: 3 Pages: 382-394

    • DOI

      10.1093/cvr/cvt106

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.2012

    • Author(s)
      Purevjav E
    • Journal Title

      Hum Mol Genet

      Volume: 21 Issue: 9 Pages: 2039-2053

    • DOI

      10.1093/hmg/dds022

    • Related Report
      2012 Annual Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prevalence and Distribution of Sarcomeric Gene Mutations in Japanese Patients With Familial Hypertrophic Cardiomyopathy2012

    • Author(s)
      Otsuka H, Arimura T, Abe T, Kawai H, Aizawa Y, Kubo T, Kitaoka H, Nakamura H, Nakamura K, Okamoto H, Ichida F, Ayusawa M, Nunoda S, Isobe M, Matsuzaki M, Doi YL, Fukuda K, Sasaoka T, Izumi T, Ashizawa N, Kimura A
    • Journal Title

      Circulation Journal

      Volume: 76 Issue: 2 Pages: 453-461

    • DOI

      10.1253/circj.CJ-11-0876

    • NAID

      10030035969

    • ISSN
      1346-9843, 1347-4820
    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A single nucleotide polymorphism in the 3'-untranslated region of MyD 88 gene is associated with Buerger disease but not with Takayasu arteritis in Japanese2011

    • Author(s)
      Chen Z, Nakajima T, Inoue Y, Kudo T, Jibiki M, Iwai T, Kimura A
    • Journal Title

      J Hum Genet

      Volume: 56 Issue: 7 Pages: 545-547

    • DOI

      10.1038/jhg.2011.44

    • NAID

      10030660317

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Contribution of genetic factors to the pathogenesis of dilated cardiomyopathy : the cause of dilated cardiomyopathy : genetic or acquired? (genetic-side)2011

    • Author(s)
      Kimura A
    • Journal Title

      Circ J

      Volume: 75 Pages: 1756-1765

    • NAID

      10029127069

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genetic Screening and Double Mutation in Japanese Patients With Hypertrophic Cardiomyopathy2011

    • Author(s)
      Kubo T, Kitaoka H, Okawa M, Baba Y, Hirota T, Hayato K, Yamasaki N, Matsumura Y, Otsuka H, Arimura T, Kimura A, Doi YL
    • Journal Title

      Circulation Journal

      Volume: 75 Issue: 11 Pages: 2654-2659

    • DOI

      10.1253/circj.CJ-10-1314

    • NAID

      10030032426

    • ISSN
      1346-9843, 1347-4820
    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Toll-like receptor 2 gene polymorphisms associated with aggressive periodontitis in Japanese2011

    • Author(s)
      Takahashi M, Chen Z, Watanabe K, Kobayashi H, Nakajima T, Kimura A, Izumi Y
    • Journal Title

      Open Dent J

      Volume: 5 Issue: 1 Pages: 190-194

    • DOI

      10.2174/1874210601105010190

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Electrocardiographic Characteristics and SCN5A Mutations in Idiopathic Ventricular Fibrillation Associated with Early Repolarization2011

    • Author(s)
      Watanabe H, Nogami A, Ohkubo K, Kawata H, Hayashi Y, Ishikawa T, Makiyama T, Nagao S, Yagihara N, Takehara N, Kawamura Y, Sato A, Okamura K, Hosaka Y, Sato M, Fukae S, Chinushi M, Oda H, Okabe M, Kimura A, Maemura K, Watanabe I, Kamakura S, Horie M, Aizawa Y, Shimizu W, Makita N
    • Journal Title

      Circ Arrhythm Electrophysiol

      Volume: 4 Issue: 6 Pages: 874-881

    • DOI

      10.1161/circep.111.963983

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dilated cardiomyopathy-associated BAG3 mutations impair the Z-disc as sembly and enhance the sensitivity to apoptosis in cardiomyocytes2011

    • Author(s)
      Arimura T, Ishikawa T, Nunoda S, Kawai S, Kimura A
    • Journal Title

      Hum Mutat

      Volume: 32 Issue: 12 Pages: 1481-1491

    • DOI

      10.1002/humu.21603

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] 肥大型心筋症および拡張型心筋症におけるタイチンA/M帯変異の意義2012

    • Author(s)
      有村卓朗
    • Organizer
      第57回日本人類遺伝学会
    • Place of Presentation
      東京
    • Year and Date
      2012-10-26
    • Related Report
      2012 Annual Research Report
  • [Presentation] Novel molecular mechanisms of idiopathic cardiomyopathy2011

    • Author(s)
      Arimura T, Kimura A
    • Organizer
      第28回国際心臓研究学会日本部会
    • Place of Presentation
      東京
    • Year and Date
      2011-12-03
    • Related Report
      2011 Annual Research Report
  • [Presentation] 心筋症:遺伝子異常からみた分子病態2011

    • Author(s)
      木村彰方
    • Organizer
      第20回小児心筋疾患学会
    • Place of Presentation
      東京
    • Year and Date
      2011-11-19
    • Related Report
      2011 Annual Research Report
  • [Presentation] BAG3変異は心筋細胞のZ帯整合性異常とアポトーシス感受性増強を介して拡張型心筋症を引き起こす2011

    • Author(s)
      有村卓朗, 石川泰輔, 布田伸一, 河合祥雄, 木村彰方
    • Organizer
      第56回日本人類遺伝学会
    • Place of Presentation
      幕張
    • Year and Date
      2011-11-10
    • Related Report
      2011 Annual Research Report
  • [Presentation] ブルガダ症候群患者に見出されたSCN3B遺伝子V110I変異とその機能解析2011

    • Author(s)
      石川泰輔, 有村卓朗, 蒔田直昌, 木村彰方
    • Organizer
      第56回日本人類遺伝学会
    • Place of Presentation
      幕張
    • Year and Date
      2011-11-10
    • Related Report
      2011 Annual Research Report
  • [Presentation] Dilated cardiomyopathy-associated BAG3 mutations impair the sarcomere assembly and increase the sensitivity to apoptosis2011

    • Author(s)
      Arimura T, Ishikawa T, Kimura A
    • Organizer
      The 14th Cardiovascular Genomics and Atherosclerosis Symposium
    • Place of Presentation
      Seoul, Korea
    • Year and Date
      2011-10-28
    • Related Report
      2011 Annual Research Report
  • [Presentation] Role of sarcolemmal membrane-associated protein (SLMAP) gene in Brugadasyndrome2011

    • Author(s)
      Ishikawa T, Arimura T, Kimura A
    • Organizer
      The 14th Cardiovascular Genomics and Atherosclerosis Symposium
    • Place of Presentation
      Seoul Korea
    • Year and Date
      2011-10-28
    • Related Report
      2011 Annual Research Report

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Published: 2011-04-06   Modified: 2018-03-28  

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