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Molecular mechanism of organ remodeling : Gene transcription and cell-cell interaction in mesenchymal

Research Project

Project/Area Number 14104012
Research Category

Grant-in-Aid for Scientific Research (S)

Allocation TypeSingle-year Grants
Research Field Circulatory organs internal medicine
Research InstitutionThe University of Tokyo

Principal Investigator

NAGAI Ryozo  The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (60207975)

Co-Investigator(Kenkyū-buntansha) MAEMURA Koji  The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (90282649)
MANABE Ichiro  The University of Tokyo, Graduate School of Medicine, Lecturer, 大学院医学系研究科, 科学技術振興特任教員 (70359628)
廣井 透雄  東京大学, 医学部附属病院, 助手 (30311624)
Project Period (FY) 2002 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥107,640,000 (Direct Cost: ¥82,800,000、Indirect Cost: ¥24,840,000)
Fiscal Year 2006: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2005: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2004: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2003: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2002: ¥23,790,000 (Direct Cost: ¥18,300,000、Indirect Cost: ¥5,490,000)
Keywordstissue remodeling / transcription factor / drug discovery / atherosclerosis / metabolic syndrome / gene engineered mouse / klotho / KLF5 / Klf5 / 心肥大 / 老化 / 線維化
Research Abstract

External stress activates local cells of the mesenchymal origin (e.g., fibroblasts and smooth muscle cells) and inflammatory cells. Interactions between these cells promote fibrosis, organ hypertrophy, and structural remodeling. These changes affect the function of organs and result in organ failure including heart failure, renal failure, and liver failure. Thus, elucidation of molecular mechanisms underlying the tissue remodeling would lead to development novel therapeutic strategies for protection of normal organ function. We identified a Kruppel-like zinc finger transcription factor BTEB2 that is important for atherosclerosis, restenosis after angioplasty, tissue fibrosis, and cardiac hypertrophy. We also found that the ageing related factor Klotho inhibits tissue remodeling of the cardiovascular system. In this research project, we have analyzed transcriptional regulation and signal transduction that control tissue remodeling. The goals of the project were : 1)elucidation of the transcription factor network involved in activation of mesenchymal cells in tissue remodeling ; 2)elucidation of signal transduction mechanisms involved in the protective function of the Klotho factor against stress in the cardiovascular system ; and 3)development of drugs targeting transcription factors and humoral factors that are important for remodeling. We demonstrated that KLF5 plays essential roles in stress responses in both cardiovascular and metabolic systems. KLF5 interacts with transcription factors, such as PPARγ and RARα, cofactors, such as p300, and apoptosis-related genes, such as PARP to control stress response and to mediate tissue remodeling. To develop novel therapeutics targeting the KLF5 molecular network, we found a synthetic retinoid Am80 disrupts the interaction between KLF5 and RARα and inhibits KLF5's function. We showed that Am80 inhibited neointima formation and atherogenesis. We also demonstrate that klotho exhibits vascular protective effects.

Report

(6 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (36 results)

All 2007 2006 2005 2004 2002 Other

All Journal Article (24 results) Publications (12 results)

  • [Journal Article] Functional Interaction between the Transcription Factor Kruppel-like Factor 5 and Poly (ADP-ribose) Polymerase-1 in Cardiovascular Apoptosis.2007

    • Author(s)
      Suzuki T
    • Journal Title

      J Biol Chem 282・13

      Pages: 9895-9901

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Relationship between the structure of SET/TAF-Ibeta/INHAT and its histone chaperone activity.2007

    • Author(s)
      Muto S
    • Journal Title

      Proc Natl Acad Sci USA 104・11

      Pages: 4285-4290

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Functional Interaction between the Transcription Factor Kruppel-like Factor 5 and Poly(ADP-ribose) Polymerase-1 in Cardiovascular Apoptosis2007

    • Author(s)
      Suzuki T
    • Journal Title

      J.Biol.Chem 282・13

      Pages: 9895-9901

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Relationship between the structure of SET/TAF-Ibeta/INHAT and its histone chaperone activity2007

    • Author(s)
      Muto S
    • Journal Title

      Proc Natl Acad Sci USA 104・11

      Pages: 4285-4290

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.2007

    • Author(s)
      Yamauchi T
    • Journal Title

      Nat Med 13・3

      Pages: 332-339

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Kruppel-like transcription factor KLFS is a key regulator of adipocyte differentiation2006

    • Author(s)
      Oishi Y
    • Journal Title

      Cell Metab 1・1

      Pages: 27-39

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] DeltaEF1 mediates TGF-beta signaling in vascular smooth muscle cell differentiation.2006

    • Author(s)
      Nishimura G
    • Journal Title

      Dev Cell 11・1

      Pages: 93-104

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Kruppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation2006

    • Author(s)
      Oishi Y
    • Journal Title

      Cell Metab 1・1

      Pages: 27-39

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] DeltaEF1 mediates TGF-beta signaling in vascular smooth muscle cell differentiation2006

    • Author(s)
      Nishimura G
    • Journal Title

      Dev Cell 11・1

      Pages: 93-104

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthetic Retinoid Am80 Reduces Scavenger Receptor Expression and Atherosclerosis in Mice by Inhibiting IL-6.2006

    • Author(s)
      Takeda N
    • Journal Title

      Arterioscler Thromb Vasc Biol 26・5

      Pages: 1177-1183

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissues Causes Macrophage Recruitment and Insulin Resistance.2006

    • Author(s)
      Kamei N
    • Journal Title

      J Biol Chem 281・36

      Pages: 26602-26614

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Synthetic Ret mold Am80 Reduces Scavenger Receptor Expression and Atherosclerosis in Mice by Inhibiting IL-62006

    • Author(s)
      Takeda N
    • Journal Title

      Arterioscler Thromb Vasc Biol

    • Related Report
      2005 Annual Research Report
  • [Journal Article] C-reactive protein induces VCAM-1 gene expression through NF-kappaB activation in vascular endothelial cells2006

    • Author(s)
      Kawanami D
    • Journal Title

      Atherosclerosis 185・1

      Pages: 39-46

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Synthetic retinoid Am80 suppresses smooth muscle phenotypic modulation and in-stent neointima formation by inhibiting KLF52005

    • Author(s)
      Fujiu K
    • Journal Title

      Circ Res 97・11

      Pages: 1132-1141

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] Significance of the transcription factor KLF5 in cardiovascular remodeling2005

    • Author(s)
      Nagai R
    • Journal Title

      J Thromb Haemost 3・8

      Pages: 1569-1576

    • Related Report
      2005 Annual Research Report
  • [Journal Article] The deacetylase HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction2005

    • Author(s)
      Matsumura T
    • Journal Title

      J Biol Chem 280・13

      Pages: 12123-12129

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Admnistration of ANG II induces iron deposition and upregulation of TGF-beta1 mRNA in the rat liver2005

    • Author(s)
      Ishizaka N
    • Journal Title

      Am J Physiol 288・4

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Kruppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation.2005

    • Author(s)
      Oishi Y
    • Journal Title

      Cell Metabolism 1・1

      Pages: 27-39

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Endothelial PAS Domain Protein 1 Gene Promotes Angiogenesis Through the Transactivatioion of Both Vascular Endothelial Growth Factor and Its Receptor, Flt-1.2004

    • Author(s)
      Takeda N
    • Journal Title

      Circ Res 95・2

      Pages: 146-153

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Vasorin, a transforming growth factor β-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo.2004

    • Author(s)
      Ikeda Y
    • Journal Title

      Proc Natl Acad Sci USA 101・29

      Pages: 10732-10737

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Protective effects of endogenous adrenomedullin on cardiac hypertrophy, fibrosis, and renal damage.2004

    • Author(s)
      Niu P
    • Journal Title

      Circulation 109・14

      Pages: 1789-1794

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Angiogenic effects of adrenomedullin in ischemia and tumor growth.2004

    • Author(s)
      Iimuro S
    • Journal Title

      Circ Res 95・4

      Pages: 415-423

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells : a new insight into adipocytokine-endothelial cell interactions.2004

    • Author(s)
      Kawanami D
    • Journal Title

      Biochem Biophys Res Commun 314・2

      Pages: 415-419

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling2002

    • Author(s)
      Shindo T
    • Journal Title

      Nat Med 8・8

      Pages: 856-863

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Publications] Aizawa, K.: "Regulation of Platelet-derived Growth Factor-A Chain by Kruppel-like Factor 5 : New Pathway of Cooperative Activation with Nuclear Factor-kB."Journal of Biological Chemistry. 279・1. 70-76 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Miyamoto, S.: "Positive and negative regulation of the cardiovascular transcription factor KLF5 by p300 and the oncogenic regulator SET through interaction and acetylation on the DNA-binding domain."Molecular Cellular Biology. 23・23. 8528-8541 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Suzuki, T.: "Functional interaction of the DNA-binding transcription factor Sp1 through its DNA-binding domain with the histone chaperone TAF-I."Journal of Biological Chemistry. 278・31. 28758-28764 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamauchi, T.: "Cloning of adiponectin receptors that mediate antidiabetic metabolic effects."Nature. 423・6941. 762-769 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanaka, K.: "Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries."Circulation Research. 93・8. 783-790 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sakamoto, H.: "Smooth muscle cell outgrowth from coronary atherectomy specimens in vitro is associated with less time to restenosis and expression of a key Transcription factor KLF5/BTEB2."Cardiology. 100・2. 80-85 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shindo T.: "Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling"Nature Medicine. 88. 856-863 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Manabe I.: "Gen Expression in Fibroblasts and Fibrosis : Involvement in Cardiac Hypertrophy"Circulation Research. 91・12. 1103-1113 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sata M.: "Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis"Nature Medicine. 8・4. 403-409 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamauchi T.: "Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice"Nature Genetics. 30・2. 221-226 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamauchi T.: "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase"Nature Medicine. 8・11. 1288-1295 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mitani H.: "In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage"Hypertension. 39・4. 838-843 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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