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発生工学を用いた心不全形成におけるgp130の役割の解析

Research Project

Project/Area Number 12136204
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionOsaka University

Principal Investigator

瀧原 圭子  大阪大学, 保健センター, 助教授 (70252640)

Co-Investigator(Kenkyū-buntansha) 廣田 久雄  大阪大学, 医学系研究科, 助手 (30273684)
藤尾 慈  大阪大学, 医学部・附属病院, 医員
国定 慶太  大阪大学, 医学系研究科, 助手 (80294057)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥64,000,000 (Direct Cost: ¥64,000,000)
Fiscal Year 2004: ¥16,700,000 (Direct Cost: ¥16,700,000)
Fiscal Year 2003: ¥16,700,000 (Direct Cost: ¥16,700,000)
Fiscal Year 2002: ¥15,300,000 (Direct Cost: ¥15,300,000)
Fiscal Year 2001: ¥15,300,000 (Direct Cost: ¥15,300,000)
Keywords心筋細胞 / サイトカイン / 心不全 / リモデリング / 幹細胞 / 情報伝達 / アポトーシス / 心筋リモデリング / 疾患モデル動物
Research Abstract

骨髄幹細胞をはじめ、さまざまな組織に存在する成体幹細胞を用いた細胞治療が、心不全の新たな治療法として注目されているが、導入細胞がどのような細胞に分化することにより心機能改善効果を示しているのか、これらのプロセスを支持する分子基盤に関しては明らかにされていない。G-CSFが心筋梗塞後のリモデリングを改善することが報告されているが、当初は、骨髄からの細胞動員の増加に伴い梗塞および周辺領域に骨髄由来細胞が集積し、心筋細胞の再生に関与していると考えられていた,我々はこれまでの研究において作製したconstitutive active STAT3を心筋特異的に高発現するトランスジェニックマウスを用い、心筋傷害/心筋リモデリングのモデルとして心筋梗塞を作製し、これらのマウスにおいて抗酸化作用やアポトーシス抑制作用により、梗塞後の心不全および生存率が有意に改善されるという結果を得た。G-CSFはかねてよりレセプターを介してSTAT3を活性化することにより、その作用を示すことが知られている。今年度は、dominant negative-type STAT3を心筋特異的に高発現するトランスジェニックマウスを用い、G-CSFの保護効果について検討した。(千葉大学、小室教授との共同研究)G-CSFの投与により心筋に存在する骨髄由来細胞の数は心筋梗塞後においてもコントロールと変化ないこと、心筋細胞にG-CSFレセプターが存在していることが明らかとなった。また、dominant negative-type STAT3トランスジェニックマウスにG-CSF投与を行ったところ、その保護効果は減弱することが明らかとなった。以上より、G-CSFはSTAT3を介して直接に心筋細胞に作用し、心筋梗塞後のリモデリングの改善効果を示すと考えられた。

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

    (32 results)

All 2005 2004 Other

All Journal Article (5 results) Book (1 results) Publications (26 results)

  • [Journal Article] G-CSF prevents cardiac remodeling after myocardial infarction by activating Jak/Stat in cardiomyocytes.2005

    • Author(s)
      M.Harada et al.
    • Journal Title

      Nature Medicine 11

      Pages: 305-311

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Novel insertional mutation in the bone morphogenetic protein receptor type II associated with sporadic primary pulmonary hypertension2004

    • Author(s)
      S.Sugiyama et al.
    • Journal Title

      Circ J 68

      Pages: 592-594

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Solitary right ventricle metastasis by renal cell carcinoma.2004

    • Author(s)
      M.Masaki et al.
    • Journal Title

      J Am Soc Echocardiogr 17

      Pages: 397-398

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Circulating interleukin-6 related cytokines and their receptors in patients with congestive heart failure.2004

    • Author(s)
      H.Hirota et al.
    • Journal Title

      Heart Vessels 19

      Pages: 237-241

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Smad1 protects cardiomyocytes from ischemia-reperfusion injury.

    • Author(s)
      M.Masaki et al.
    • Journal Title

      Circulation (in press)

    • Related Report
      2004 Annual Research Report
  • [Book] 医学のあゆみ別冊「サイトカイン-State of Arts-」2004

    • Author(s)
      瀧原 圭子
    • Total Pages
      4
    • Publisher
      医師薬出版
    • Related Report
      2004 Annual Research Report
  • [Publications] M.Kawai et al.: "Ral GDP dissociation stimulator and Ral GTPase are involved in myocardial hypertrophy."Hypertension. 41. 956-962 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Kuwasako et al.: "Lipoprotein abnormalities in human genetic CD36 deficiency associated with insulin resistance and abnormal fatty acid metabolism."Diabetes Care. 26. 1647-1648 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Y.Nakaoka et al.: "Activation of gp130 transduces hypertrophic signal through interaction of scafolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes."Circ Res. 93. 221-229 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] K.Yamauchi-Takihara: "Complexity of transcriptional regulation of the tumor necrosis factor-alpha gene."J Mol Cell Cardiol. 35. 1179-1181 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] H.Hirota et al.: "Circulating interleukin-6 related cytokines and their receptors in patients with congestive heart failure."Heart Vessels. in press.

    • Related Report
      2003 Annual Research Report
  • [Publications] K.Yamauchi-Takihara et al.: "A novel role for cytokine signaling in cardiac remodeling. In : Cardiac Remodeling and Failure."Kluwer Academic Publishers. 350 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Osugi, et al.: "Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart"J Biol Chem. 277. 6676-6681 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] K.Kunisada, et al.: "Bcl-xl reduces doxorubicin-induced myocardial damage but fails to control cardiac gene downregulation"Cardiovasc Res. 53. 936-943 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] E.Hatzi, et al.: "N-myc oncogene overexpression down-regulates IL-6 ; evidence that IL-6 inhibits angiogenesis and supresses neuroblastoma tumor growth"Oncogene. 21. 3552-3561 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] M.Shirai, et al.: "The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis"J Clin Invest. 110. 177-184 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Y.Oshima, et al.: "Aldosterone augments endothelin-I-induced cardiac myocyte hypertrophy with the reinforcement of JNK pathway"FEBS Lett. 524. 123-126 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] K.Yamauchi-Takihara: "gp130-mediated pathway and left ventricular remodeling"J Card Fail. 8. S374-S378 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 瀧原 圭子: "IL-6サイトカインファミリー「循環器病フロンティア ベーシック&クリニカルサイエンス」"小室 一成編 メジカルビュー社. 176-182 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] S.Negoro et al.: "Glycoprotein130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through P13-kinase/Akt phosphorylation and Bcl-xL/Caspase-3 interaction"Circulation. 103. 555-561 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Izumi et al.: "Bone morphogenic protein-2 inhibits serum deprivation-induced apoptosis of neonatal cardiac myocytes through the activation of smad1 pathway"J.Biol.Chem.. 276. 31133-31141 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] S.Negoro et al.: "Activation of STAT3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase"Circulation. 104. 979-981 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Osugi et al.: "Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart"J.Biol.Chem.. 277. 6676-6681 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Kunisada et al.: "Bcl-xl reduces doxorubicin-induced myocardial damage but fails to control cardiac gene downregulation"Cardiovasc Res.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Yamauchi-Takihara: "gp130 mediated pathway and LV remodeling"J.Card Fail. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 瀧原圭子: "gp13 心筋細胞増殖および保護における役割 「心臓における生命現象の分子生物学」"小室一成編. 181-188 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Funamoto et al.: "Signal transducer and activator of transcription 3 is required for glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes."J.Biol.Chem.. 275. 10561-10566 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Okuno et al.: "Expressional patterns of cytokines in a murine model of acute myocarditis : early expression of cardiotrophin-1"Lab.Invest.. 80. 433-440 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Funamoto et al.: "Isolation and characaterization of the murine cardiotrophin-1 gene. -Expression and norepinephrine induced transcriptional activation-"J.Mol.Cell.Cardiol.. 32. 1275-1284 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Negoro et al.: "Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction"Cardiovase.Res.. 47. 797-805 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] E.Tone et al.: "gp130-dependent signaling pathway is not enhanced in gp130 transgenic heart after LIF stimulation"CYTOKINE. 12. 1512-1518 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Negoro et al.: "gp130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through PI3-kinase/A kt phosphorylation and Bcl-xL/Caspase-3 interaction"Circulation. 103. 555-561 (2001)

    • Related Report
      2000 Annual Research Report

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

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