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Development of New Treatment Strategies of Cardiovascular Pathologies by Using Epigenetic Regulation

Research Project

Project/Area Number 20390219
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionThe University of Tokyo

Principal Investigator

SUZUKI Toru  The University of Tokyo, 医学部附属病院, 特任准教授 (90359620)

Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2010: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2009: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2008: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
Keywords循環器・高血圧 / ストレス / 蛋白質 / トランスレーショナル・リサーチ / プロテオーム / エピジェネティクス / プロテオミクス / 転写因子 / 循環器 / 心血管疾患 / クロマチン転写
Research Abstract

The pathogenesis of lifestyle diseases such as cardiovascular disease is more closely related to environmental factors than genetic factors. In other words, the changes in gene function and cellular phenotype lacking any changes in genomic sequence, known as epigenetic regulation, is considered to be responsible for the pathogenesis. Epigenetic regulation in the cardiovascular system, however, has not been sufficiently understood. We expected that the changes in chromatin structure would lead us towards a greater understanding of the mechanism of regulation of transcription in eukaryotes and discovered the interactions between DNA binding proteins and chromatin structural changes and their functional significance. We hypothesized that by focusing on cardiovascular epigenetic regulation, this study will explain how transcription in chromatin and DNA repair is regulated in cardiovascular disease and will contribute to drug discovery. In order to address epigenetic regulation in cardiovas … More cular disease, we studied KLF5, a key factor of this disease, and discovered molecules, such as ANP32B, which interact with KLF5. In addition to these interactive factors, we analyzed the function of ATM and H2AX, the key factors for DNA repair that we considered were important, by employing molecular biological and genetic engineering techniques (e.g. the generation of knockout mice) and disease animal models (e.g. vascular senescence models). As a result, (i) by examining the regulation of the histone chaperone family, we found a novel histone chaperone ANP32B, and its structural analysis revealed that ANP32B regulates the amount of histone in the promoter region of KLF5 downstream genes (Munemasa et al.2008). We also solved the crystal structure of (Tochio et al.2010). (ii) The analysis of the new regulative mechanism of vascular senescence by ATM showed that ATM plays an important role in oxidative stress-induced endothelial dysfunction and premature senescence through the Akt/p53/p21 pathway. Our research revealed the molecular mechanisms of epigenetic regulation in human pathology. Importantly, it is possible that these mechanisms may lead to new treatments, and new studies based on our results. Less

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (47 results)

All 2010 2009 2008 Other

All Journal Article (18 results) (of which Peer Reviewed: 15 results) Presentation (21 results) Book (2 results) Remarks (5 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] In search of blood tests for thoracic aortic diseases.2010

    • Author(s)
      Trimarchi S, Sangiorgi G, Sang X, Rampoldi V, Suzuki T, Eagle KA, Elefteriades JA.
    • Journal Title

      Ann Thorac Surg 90(5)

      Pages: 1735-1742

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Biomarker-assisted diagnosis of acute aortic dissection ; how far we have come and what to expect.2010

    • Author(s)
      Suzuki T, Distante A, Eagle KA.
    • Journal Title

      Curr Opin Cardiol 25(6)

      Pages: 541-545

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Ataxia telangiectasia mutated (ATM)-mediated DNA damage response in oxidative stress-induced vascular endothelial cell senescence.2010

    • Author(s)
      Zhan H, Suzuki T, Aizawa K, Miyagawa K, Nagai R
    • Journal Title

      J Biol Chem 285

      Pages: 29662-29670

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Response to letter regarding article, "Diagnosis of acute aortic dissection by D-dimer ; the IRAD-Bio experience".2010

    • Author(s)
      Suzuki T, Distante A, Zizza A, Trimarchi S, Villani M, Antonio J, Salerno Uriarte JA, de Luca Tupputi Schinosa L, Renzulli A, Sabino F, Nowak R, Birkhahn R, Hollander J, Counselman F, Vijayendran R, Bossone E, Eagle K.
    • Journal Title

      Circulation 121

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Solution Structure of Histone Chaperone ANP32B : Interaction with Core Histones H3-H4 through Its Acidic Concave Domain.2010

    • Author(s)
      Tochio N, Umehara T, Munemasa Y, Suzuki T, Sato S, Tsuda K, Koshiba S, Kigawa T, Nagai R, Yokoyama S.
    • Journal Title

      J Mol Biol. 401

      Pages: 97-114

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] 診断の進歩;バイオマーカー2010

    • Author(s)
      鈴木亨、澤城大悟、永井良三
    • Journal Title

      日本内科学会雑誌 Vol.99、No.2

      Pages: 269-274

    • Related Report
      2010 Final Research Report
  • [Journal Article] Ataxia telangiectasia mutated (ATM)-mediated DNA damage response in oxidative stress-induced vascular endothelial cell senescence.2010

    • Author(s)
      Zhan H, Suzuki T, Aizawa K, Miyagawa K, Nagai R
    • Journal Title

      J Biol Chem

      Volume: 285 Pages: 29662-29670

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Solution structure of histone chaperone ANP32B : interaction with core histones H3-H4 through its acidic concave domain.2010

    • Author(s)
      Tochio N, Umehara T, Munemasa Y, Suzuki T, Sato S, Tsuda K, Koshiba S, Kigawa T, Nagai R, Yokoyama S
    • Journal Title

      J Mol Biol

      Volume: 401 Pages: 197-114

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] for the IRAD-Bio Investigators. Diagnosis of acute aortic dissection by D-Dimer. The International Registry of Acute Aortic Dissection substudy on biomarkers (IRAD-Bio) experience.2009

    • Author(s)
      Suzuki T, Distante A, Zizza A, Trimarchi S, Villani M, Salerno Uriarte JA, de Luca Tupputi Schinosa L, Renzulli A, Sabino F, Nowak R, Birkhahn R, Hollander JE, Counselman F, Vijayendran R, Bossone E, Eagle K
    • Journal Title

      Circulation 119(20)

      Pages: 2702-2707

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Cardiovascular diagnostic biomarkers-The past, present and future-.2009

    • Author(s)
      鈴木亨
    • Journal Title

      Circ J 73(5)

      Pages: 806-809

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Kruppel-like factor 5 shows proliferation-specific roles in vascular remodeling, direct stimulation of cell growth, and inhibition of apoptosis.2009

    • Author(s)
      Suzuki T, Sawaki D, Aizawa K, Munemasa Y, Matsumura T, Ishida J, Nagai R
    • Journal Title

      J Biol Chem 284(14)

      Pages: 9549-9557

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] プロテオミクス手法を用いた心血管系酸化ストレスの病態解明2009

    • Author(s)
      鈴木亨
    • Journal Title

      代謝異常治療研究基金研究業績集 36巻

      Pages: 97-103

    • Related Report
      2010 Final Research Report
  • [Journal Article] 解説;IRAD、その成績と意義2009

    • Author(s)
      鈴木亨、澤城大悟
    • Journal Title

      循環器科 Vol.66、No.5

      Pages: 561-566

    • Related Report
      2010 Final Research Report
  • [Journal Article] Regulation of transforming growth factor-β-dependent cyclooxygenase-2 expression in fibroblasts2009

    • Author(s)
      Matsumura T, Suzuki T, Aizawa K, Sawaki D, Munemasa Y, Ishida J, Nagai R
    • Journal Title

      J Biol Chem 284

      Pages: 35861-35871

    • NAID

      40019431619

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Kruppel-like factor 5 shows proliferation-specific roles in vascular remodeling, directstimulation of cell growth and inhibition of apoptosis.2009

    • Author(s)
      Suzuki T
    • Journal Title

      J Biol Chem 284

      Pages: 9549-9577

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] International Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-Bio) Investigators. Preliminary experience with the smooth muscle troponin-like protein, calponin, as a novel biomarker for diagnosing acute aortic dissection.2008

    • Author(s)
      Suzuki T, Distante A, Zizza A, Trimarchi S, Villani M, Salerno Uriarte JA, de Luca Tupputi Schinosa L, Renzulli A, Sabino F, Nowak R, Birkhahn R, Hollander JE, Counselman F, Bossone E, Eagle K
    • Journal Title

      Eur Heart J 29(11)

      Pages: 1439-1445

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Molecular markers for cardiovascular disease : cardiovascular biomarkers to proteomic discovery.2008

    • Author(s)
      鈴木亨, 永井良三
    • Journal Title

      Nat Clin Pract Cardiovasc Med 5(6)

      Pages: 295-295

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Circulating TGFbeta levels in acute aortic dissection.

    • Author(s)
      Suzuki T, Trimarchi S, Sawaki D, Grassi V, Costa E, Rampoldi V, Nagai R, Eagle KA.
    • Journal Title

      J Am Coll Cardiol in press

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Presentation] Epigenetic regulation of disease biology .focus on the role of ATM and the DNA-damage response in the cardiovasculature.2010

    • Author(s)
      鈴木亨
    • Organizer
      第33回日本分子生物学会年会・第83回日本生化学会大会合同大会(Interface between nuclear dynamics and diseases)
    • Place of Presentation
      神戸(シンポジウム)
    • Related Report
      2010 Final Research Report
  • [Presentation] Epigenetic regulation of chromatin transcription-KLFs as a model system.2010

    • Author(s)
      鈴木亨
    • Organizer
      2010 FASEB Summer Research Conferences
    • Place of Presentation
      Steamboat Springs, CO, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Proteomic analysis of the vasculature.2010

    • Author(s)
      鈴木亨
    • Organizer
      16th International vascular Biology Meeting
    • Place of Presentation
      Los Angeles, CA, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Proteomic analysis of the vasculature2010

    • Author(s)
      Suzuki T
    • Organizer
      16th International vascular Biology Meeting
    • Place of Presentation
      Los Angeles, CA, USA
    • Related Report
      2010 Annual Research Report
  • [Presentation] Epigenetic regulation of chromatin transcription-KLFs as a model system2010

    • Author(s)
      Suzuki T
    • Organizer
      2010 FASEB Summer Research Conferences
    • Place of Presentation
      Steamboat Springs, CO, USA
    • Related Report
      2010 Annual Research Report
  • [Presentation] Epigenetic regulation of disease biology-focus on the role of ATM and the DNA-damage response in the cardiovasculature2010

    • Author(s)
      鈴木亨
    • Organizer
      第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
    • Place of Presentation
      神戸
    • Related Report
      2010 Annual Research Report
  • [Presentation] Oxidative Stress-induced Premature Cell Senescence is Mediated by Ataxia Telangiectasia Mutated in Vascular Endothelial Cells2010

    • Author(s)
      Aizawa K, Suzuki T, Zhan H, Matsumura T, Sawaki D, Ishida J, Miyagawa K, Nagai R
    • Organizer
      第74回日本循環器学会総会・学術集会
    • Place of Presentation
      京都
    • Related Report
      2009 Annual Research Report
  • [Presentation] Kruppel-like Factor 6 Mediates Angiotensin II and TGFβ Signaling in Cardiovascular Pathologies2010

    • Author(s)
      Sawaki D, Suzuki T, Aizawa K, Matsumura T, Munemasa Y, Ishida J, Friedman S, Nagai R
    • Organizer
      第74回日本循環器学会総会・学術集会
    • Place of Presentation
      京都
    • Related Report
      2009 Annual Research Report
  • [Presentation] 細胞核の機能制御異常による心血管病態の解析2009

    • Author(s)
      鈴木亨
    • Organizer
      日本放射線影響学会第52回大会(ワークショップ:細胞核からみた放射線病態学)
    • Place of Presentation
      広島
    • Related Report
      2010 Final Research Report
  • [Presentation] The potential for development of a circulating marker for acute aortic dissection : opportunities and challenges.2009

    • Author(s)
      鈴木亨
    • Organizer
      Aortic Diseases Summit
    • Place of Presentation
      Baltimore, ML, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Genetics of fibrillinopathies.2009

    • Author(s)
      鈴木亨
    • Organizer
      Advances in Understanding Aortic Diseases
    • Place of Presentation
      Hamburg, Germany
    • Related Report
      2010 Final Research Report
  • [Presentation] Biomarkers as a new diagnostic option2009

    • Author(s)
      鈴木亨
    • Organizer
      Advances in Understanding Aortic Diseases
    • Place of Presentation
      Hamburg, Germany
    • Related Report
      2010 Final Research Report
  • [Presentation] Current approaches to aortic dissection ; from biomarkers to the international registry of acute aortic dissection (IRAD).2009

    • Author(s)
      鈴木亨
    • Organizer
      第73回日本循環器学会学術集会
    • Place of Presentation
      大阪
    • Related Report
      2010 Final Research Report
  • [Presentation] 細胞核の機能制御異常による心血管病態の解析2009

    • Author(s)
      鈴木亨
    • Organizer
      日本放射線影響学会第52回大会
    • Place of Presentation
      広島
    • Related Report
      2009 Annual Research Report
  • [Presentation] Kruppel-like facter 6 is a key transcription factor in adipocyte differentiation2009

    • Author(s)
      Ishida J, Suzuki T, Aizawa K, Sawaki D, Matsumura T, Nagai R
    • Organizer
      American Heart Association 82nd Scientific Sessions
    • Place of Presentation
      Orland, FL, USA
    • Related Report
      2009 Annual Research Report
  • [Presentation] プロテオミクス解析法を用いた心血管病態におけるKLF5転写複合体を介した新規経路の同定2009

    • Author(s)
      相澤健一、鈴木亨、〓紅、松村貴由、石田純一、澤城大悟、宗政歓子、永井良三
    • Organizer
      第46回日本臨床分子医学会学術集会
    • Place of Presentation
      東京
    • Related Report
      2009 Annual Research Report
  • [Presentation] Positive regulation of promoter-region specific histone incorporation by histone chaperones ANP32B and TAF-I, histone deacetylase HDAC1 and DNA-binding factor KLF52009

    • Author(s)
      宗政歓子、鈴木亨、相澤健一、松村貴由、澤城大悟、永井良三
    • Organizer
      第46回日本臨床分子医学会学術集会
    • Place of Presentation
      東京
    • Related Report
      2009 Annual Research Report
  • [Presentation] Epigenetic control of gene transcription at the chromatin level with a focus on Kruppel-like factors.2008

    • Author(s)
      Suzuki T, Aizawa K, Munemasa Y, Matsumura T, Sawaki D, Kada N, Nagai R
    • Organizer
      15th International Vascular Biology Meeting
    • Place of Presentation
      Sydney, Australia
    • Related Report
      2010 Final Research Report
  • [Presentation] Epigenetic control of gene transcription at the chromatin level with a focus on Kruppel-like factors.2008

    • Author(s)
      鈴木亨
    • Organizer
      15th International Vascular Biology Meeting
    • Place of Presentation
      Sydney, Australia.
    • Related Report
      2010 Final Research Report
  • [Presentation] Epigenetic control of gene transcription at the chromatin level with a focus on kruppel-like factors.2008

    • Author(s)
      Suzuki T
    • Organizer
      15th International Vascular Biology Meeting
    • Place of Presentation
      Sydney, Australia
    • Related Report
      2008 Annual Research Report
  • [Presentation] ヒストンシャペロンANP32B,TAF-IとDNA結合型転写因子KLF5によるプロモーター特異的ヒストン量制御2008

    • Author(s)
      宗政歓子
    • Organizer
      第31回日本分子生物学会年会/第81回日本生化学会大会合同大会
    • Place of Presentation
      神戸
    • Related Report
      2008 Annual Research Report
  • [Book] 新しい酸化LDLの測定法(「別冊・医学のあゆみ、心血管マルチバイオマーカー・ストラテジー」)(清野精彦監修)2009

    • Author(s)
      鈴木亨, 他
    • Publisher
      医歯薬出版
    • Related Report
      2010 Final Research Report
  • [Book] Annual Review 2008循環器(DNA損傷と修復)(山口徹、高本眞一、中澤誠、小室一成監修)2008

    • Author(s)
      鈴木亨, 他
    • Publisher
      中外医学社
    • Related Report
      2010 Final Research Report
  • [Remarks] ホームページ等

    • Related Report
      2010 Final Research Report
  • [Remarks] 東京大学大学院医学系研究科ユビキタス予防医学講座

    • URL

      http://plaza.umin.ac.jp/upm/index.html

    • Related Report
      2010 Final Research Report
  • [Remarks]

    • URL

      http://plaza.umin.ac.jp/upm/

    • Related Report
      2010 Annual Research Report
  • [Remarks]

    • URL

      http://plaza.umin.ac.jp/upm/

    • Related Report
      2009 Annual Research Report
  • [Remarks]

    • URL

      http://plaza.umin.ac.jp/upm/

    • Related Report
      2008 Annual Research Report
  • [Patent(Industrial Property Rights)] 血液試料を用いて心筋虚血状態を評価する方法2008

    • Inventor(s)
      鈴木亨、藤本宏隆
    • Industrial Property Rights Holder
      国立大学法人東京大学、株式会社島津製作所
    • Filing Date
      2008-08-28
    • Related Report
      2010 Final Research Report
    • Overseas

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Published: 2008-04-01   Modified: 2016-04-21  

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