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Role of Wnt signaling in cardiomyocyte differentiation and its implication for the treatment of heart diseases

Research Project

Project/Area Number 21229010
Research Category

Grant-in-Aid for Scientific Research (S)

Allocation TypeSingle-year Grants
Research Field Circulatory organs internal medicine
Research InstitutionThe University of Tokyo (2013)
Osaka University (2010-2012)
Chiba University (2009)

Principal Investigator

KOMURO Issei  東京大学, 医学部附属病院, 教授 (30260483)

Co-Investigator(Kenkyū-buntansha) NAGAI Toshio  千葉大学, 大学院・医学薬学府, 准教授 (00334194)
塩島 一朗  大阪大学, 大学院・医学糸研究科, 寄附講座准教授 (90376377)
Project Period (FY) 2009-05-11 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥211,770,000 (Direct Cost: ¥162,900,000、Indirect Cost: ¥48,870,000)
Fiscal Year 2013: ¥32,240,000 (Direct Cost: ¥24,800,000、Indirect Cost: ¥7,440,000)
Fiscal Year 2012: ¥33,280,000 (Direct Cost: ¥25,600,000、Indirect Cost: ¥7,680,000)
Fiscal Year 2011: ¥33,280,000 (Direct Cost: ¥25,600,000、Indirect Cost: ¥7,680,000)
Fiscal Year 2010: ¥49,920,000 (Direct Cost: ¥38,400,000、Indirect Cost: ¥11,520,000)
Fiscal Year 2009: ¥63,050,000 (Direct Cost: ¥48,500,000、Indirect Cost: ¥14,550,000)
Keywords循環器・高血圧 / 発生・分化 / Wntシグナル / iPS細胞 / 間葉系幹細胞 / 心不全 / 心筋細胞 / 多能性幹細胞 / 心筋細胞分化 / Wnt / C1q / ES細胞 / IGFBP-4
Research Abstract

Patients with heart diseases are increasing in number, and elucidation of the pathophysiology and development of novel therapeutic strategies for heart diseases are mandatory. Wnt signaling pathway plays multiple roles in development and diseases, and recent studies have also implicated Wnt signaling both in heart development during embryogenesis and heart diseases in the adult. In the present study, we have clarified the molecular mechanism how IGFBP4 inhibits Wnt signaling and promotes heart development. We have also identified that activation of Wnt signaling followed by inhibition of Wnt signaling by using small molecules can efficiently induce cardiac differentiation of human iPS cells and mouse mesenchymal stem cells. Finally, we have identified that complement protein C1q is increased in the serum of heart failure model mice and may play detrimental role in the progression of heart failure.

Assessment Rating
Verification Result (Rating)

A-

Report

(7 results)
  • 2014 Research Progress Assessment (Verification Result) ( PDF )
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (44 results)

All 2013 2012 2011 2010 2009 Other

All Journal Article (21 results) (of which Peer Reviewed: 19 results,  Open Access: 1 results) Presentation (18 results) (of which Invited: 8 results) Book (3 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] PEARL Study Investigators Effects of pitavastatin in Japanese patients with chronic heart failure.2013

    • Author(s)
      Takano H, Komuro I (11人中11番目)
    • Journal Title

      Circulation Journal

      Volume: 77 Pages: 917-925

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ras Homologue Enriched in Brain (Rheb)-dependent mTORC1 Activation Becomes Indispensable for Cardiac Hypertrophic Growth after Early Postnatal Period.2013

    • Author(s)
      Tamai T, Komuro I (17人中16番目)
    • Journal Title

      J Biol Chem

      Volume: 288 Issue: 14 Pages: 10176-10187

    • DOI

      10.1074/jbc.m112.423640

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prognostic impact of left ventricular noncompaction in patients with Duchenne/Becker muscular dystrophy - Prospective multicenter cohort study2013

    • Author(s)
      Kimura K, Komuro I (21人中21番目)
    • Journal Title

      Int J Cardiol

      Volume: 168 Issue: 3 Pages: 1900-1904

    • DOI

      10.1016/j.ijcard.2012.12.058

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] AngiotensinIIType 2 Receptor-induced Cell Signaling.2013

    • Author(s)
      Akazawa H, Komuro I (5人中5番目)
    • Journal Title

      Curr Pharm Des.

      Volume: 19 Pages: 3002-3008

    • Related Report
      2013 Annual Research Report
  • [Journal Article] Class-and Molecule-specific Differential Effects of AngiotensinIIType 1 Receptor Blockers.2013

    • Author(s)
      Imaizumi S and Komuro I (6人中5番目)
    • Journal Title

      Curr Pharm Des.

      Volume: 19 Pages: 3002-3008

    • Related Report
      2013 Annual Research Report
  • [Journal Article] A Novel Heart Failure Mice Model of Hypertensive Heart Disease by Angiotensin II Infusion, Nephrectomy, and Salt Loading2013

    • Author(s)
      Tsukamoto Y, Komuro I(15人中15番目)
    • Journal Title

      Am J Physiol Heart Circ Physiol.

      Volume: 305 Issue: 11 Pages: 1658-1667

    • DOI

      10.1152/ajpheart.00349.2013

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Interleukin-16 promotes cardiac fibrosis and myocardial stiffening in heart failure with preserved ejection fraction.2013

    • Author(s)
      Tamaki S, Komuro I (19人中19番目)
    • Journal Title

      PLoS One

      Volume: 8 Issue: 7 Pages: e68893-e68893

    • DOI

      10.1371/journal.pone.0068893

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction.2013

    • Author(s)
      Matsumoto S, Komuro I (11人中11番目)
    • Journal Title

      Circ Res.

      Volume: 113 Issue: 3 Pages: 322-326

    • DOI

      10.1161/circresaha.113.301209

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Toll-like receptor-2 mediates adaptive cardiac hypertrophy in response to pressure overload through interleukin-1β upregulation via nuclear factor κB activation.2013

    • Author(s)
      Higashikuni Y and Komuro I(8人中7番目)
    • Journal Title

      J Am Heart Assoc

      Volume: 2 Issue: 6

    • DOI

      10.1161/jaha.113.000267

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sarcomere Gene Mutations Are Associated With Increased Cardiovascular Events in Left Ventricular Hypertrophy : Results From Multicenter Registration in Japan.2013

    • Author(s)
      Fujita T, Komuro I (18人中13番目)
    • Journal Title

      JACC Heart Fail

      Volume: 6 Issue: 6 Pages: 459-466

    • DOI

      10.1016/j.jchf.2013.08.007

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes2012

    • Author(s)
      Naito AT, Sumida T, Nomura S, Liu ML, Higo T, Nakagawa A, Okada K, Sakai T, Hashimoto A, Hara Y, Shimizu I, Zhu W, Toko H, Katada A, Akazawa H, Oka T, Lee JK, Minamino T, Nagai T, Walsh K, Kikuchi A, Matsumoto M, Botto M, Shiojima I, Komuro I
    • Journal Title

      Cell

      Volume: 149 Issue: 6 Pages: 1298-1313

    • DOI

      10.1016/j.cell.2012.03.047

    • Related Report
      2013 Final Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure2012

    • Author(s)
      Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, Akira S, Yamamoto A, Komuro I, Otsu K
    • Journal Title

      Nature

      Volume: 485 Issue: 7397 Pages: 251-255

    • DOI

      10.1038/nature10992

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] A crucial role of activin A-mediated growth hormone suppression in mouse and human heart failure2011

    • Author(s)
      Fukushima N, Matsuura K, Akazawa H, Honda A, Nagai T, Takahashi T, Seki A, Murasaki KM, Shimizu T, Okano T, Hagiwara N, Komuro I
    • Journal Title

      PLoS One

      Volume: 6 Issue: 12 Pages: e27901-e27901

    • DOI

      10.1371/journal.pone.0027901

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Promotion of CHIP-mediated p53 degradation protects the heart from ischemic injury2010

    • Author(s)
      Naito AT, Okada S, Minamino T, Iwanaga K, Liu ML, Sumida T, Nomura S, Sahara N, Mizoroki T, Takashima A, Akazawa H, Nagai T, Shiojima I, Komuro I
    • Journal Title

      Circ Res

      Volume: 106 Issue: 11 Pages: 1692-1702

    • DOI

      10.1161/circresaha.109.214346

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Wnt signaling and aging-related heart disorders2010

    • Author(s)
      Naito AT, Komuro I, et al
    • Journal Title

      Circulation Research

      Volume: 107 Pages: 1295-1303

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice2009

    • Author(s)
      Matsuura K, Honda A, Nagai T, Fukushima N, Iwanaga K, Tokunaga M, Shimizu T, Okano T, Kasanuki H, Hagiwara N, Komuro I
    • Journal Title

      J Clin Invest

      Volume: 119 Pages: 2204-2217

    • DOI

      10.1172/jci37456

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] PDK1 coordinates survival pathways and beta-adrenergic response in the heart2009

    • Author(s)
      Ito K, Komuro I, et al.
    • Journal Title

      Proc Natl Acad Sci 106

      Pages: 8689-8694

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Interaction of myocardial insulin receptor and IGF receptor signaling in exercise-induced cardiac hypertrophy2009

    • Author(s)
      Ikeda H, Komuro I, et al.
    • Journal Title

      J Mol Cell Cardiol 47

      Pages: 664-675

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Racl activity2009

    • Author(s)
      Yoshida, M, Komuro I, et al.
    • Journal Title

      J Mol Cell Cardiol 47

      Pages: 698-705

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Multivalent ligand-receptor interactions elicit inverse agonist activity of AT(1) receptor blockers against stretch-induced AT(1) receptor activation2009

    • Author(s)
      Qin Y, Komuro I, et al.
    • Journal Title

      Hypertens Res 32

      Pages: 875-883

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A crucial role for adipose tissue p53 in the regulation of insulin resistance.2009

    • Author(s)
      Minamino T, Komuro I, et al.
    • Journal Title

      Nature Medicine 15

      Pages: 1082-1087

    • NAID

      40017207607

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Presentation] Regenerating Injured Myocardium Cardiac Angiogenesis and Myogenesis2013

    • Author(s)
      Issei Komuro
    • Organizer
      KEYSTONE SYMPOSIA
    • Place of Presentation
      Utah, USA
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Wnt Signaling in the Failing Heart2013

    • Author(s)
      Issei Komuro
    • Organizer
      ISHR XXI WORLD CONGRESS
    • Place of Presentation
      San Diego, USA
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Wnt Signaling in the Failing Heart2013

    • Author(s)
      Issei Komuro
    • Organizer
      Basic Cardiovascular Conference 2013
    • Place of Presentation
      Las Vegas, USA
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Molecular mechanisms of heart failure2013

    • Author(s)
      Issei Komuro
    • Organizer
      Wihuri Research Lnstitute Symposium on Cardiovascular Biology
    • Place of Presentation
      Helsinki, FInland
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Genetic and Molecular Determinants of Angiogenesis and Heart Failure2013

    • Author(s)
      Issei Komuro
    • Organizer
      11th Japan-Korea Joint symposium on Vascular Bioligy
    • Place of Presentation
      Jeju, Korea
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 心不全の発症機序の解明2012

    • Author(s)
      小室一成
    • Organizer
      第16回日本心血管内分泌学会学術総会
    • Place of Presentation
      東京
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] 補体は老化にともなう臓器障害に関与する2012

    • Author(s)
      小室一成
    • Organizer
      第35回日本分子生物学会年会
    • Place of Presentation
      福岡
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] Complement C1q activates canonical Wnt signaling and Promotes aging-related phenotypes2012

    • Author(s)
      Komuro I
    • Organizer
      EMBO Conference: 30 Years of Wnt Signalling
    • Place of Presentation
      Egmond aan Zee, Netherland
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] Harmful Effects of Excessive Insulin Signaling in a Setting of Pressure Overload2011

    • Author(s)
      Issei Komuro
    • Organizer
      American Heart Association 2011
    • Place of Presentation
      Orlando, USA
    • Related Report
      2013 Final Research Report
  • [Presentation] Wnt signaling and age-associated diseases2010

    • Author(s)
      小室一成
    • Organizer
      Basic Cardiovascular Science 2010
    • Place of Presentation
      Rancho Mirage (USA)(招待講演)
    • Year and Date
      2010-07-21
    • Related Report
      2010 Annual Research Report
  • [Presentation] A novel cardiomyocyte differentiation factor2010

    • Author(s)
      Issei Komuro
    • Organizer
      XXth World Congress of the International Society for Heart Research 2010 Kyoto
    • Place of Presentation
      Kyoto, Japan
    • Related Report
      2013 Final Research Report
  • [Presentation] Featured Lecture : Wnt Signaling and Age-Associated Diseases2010

    • Author(s)
      Issei Komuro
    • Organizer
      Basic Cardiovascular Sciences 2010 Scientific Sessions
    • Place of Presentation
      Rancho Mirage, USA
    • Related Report
      2013 Final Research Report
  • [Presentation] スタチンの心不全・心房細動に及ぼす効果2009

    • Author(s)
      小室一成
    • Organizer
      第13回日本心不全学会学術集会
    • Place of Presentation
      福岡
    • Year and Date
      2009-10-30
    • Related Report
      2009 Annual Research Report
  • [Presentation] Molecular Mechanisms and Novel Treatments For Heart Failure2009

    • Author(s)
      小室一成
    • Organizer
      第15回日本遺伝子治療学会
    • Place of Presentation
      大阪
    • Year and Date
      2009-07-10
    • Related Report
      2009 Annual Research Report
  • [Presentation] Regeneration Therapy for Heart Failure2009

    • Author(s)
      小室一成
    • Organizer
      9^<th> World Congress on Inflammation
    • Place of Presentation
      東京
    • Year and Date
      2009-07-09
    • Related Report
      2009 Annual Research Report
  • [Presentation] 心不全の新しい発症機序と治療2009

    • Author(s)
      小室一成
    • Organizer
      日本循環器学会北海道地方会
    • Place of Presentation
      北海道
    • Year and Date
      2009-06-13
    • Related Report
      2009 Annual Research Report
  • [Presentation] Regeneration Therapy for Heart Failure2009

    • Author(s)
      小室一成
    • Organizer
      ISHNE2009
    • Place of Presentation
      神奈川
    • Year and Date
      2009-06-04
    • Related Report
      2009 Annual Research Report
  • [Presentation] 心不全の新しい発症機序と治療2009

    • Author(s)
      小室一成
    • Organizer
      第46回日本臨床分子医学会
    • Place of Presentation
      東京
    • Year and Date
      2009-04-12
    • Related Report
      2009 Annual Research Report
  • [Book] Novel therapeutic targets and stragegies against myocardial diseases In: Hill JA, Olson EN, eds. Muscle: Fundamental biology and mechanisms of disease.2012

    • Author(s)
      Naito AT, Shiojima I, Komuro I
    • Publisher
      Elsevier Inc.
    • Related Report
      2013 Final Research Report
  • [Book] Muscle: Fundamental biology and mechanisms of disease.2012

    • Author(s)
      Naito AT
    • Total Pages
      1468
    • Publisher
      Elsevier Inc.
    • Related Report
      2012 Annual Research Report
  • [Book] 診療に活かす心機能評価2009

    • Author(s)
      塩島一朗、小室一成
    • Total Pages
      3
    • Publisher
      羊土社
    • Related Report
      2009 Annual Research Report
  • [Remarks] 大阪大学大学院医学系研究科 循環器内科学

    • URL

      http://www.med.osaka-u.ac.jp/pub/cardiology/

    • Related Report
      2012 Annual Research Report
  • [Patent(Industrial Property Rights)] インスリン様増殖因子結合タンパク質を含有するWnt シグナル伝達阻害剤2009

    • Inventor(s)
      小室一成, 塩島一朗, 朱偉東
    • Industrial Property Rights Holder
      国立大学法人千葉大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2009-04-23
    • Related Report
      2013 Final Research Report
    • Overseas

URL: 

Published: 2009-04-01   Modified: 2019-07-29  

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