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Dissecting the molecular mechanisms for SARS receptor ACE2-mediatedlung protection in ARDS/acute lung injury

Research Project

Project/Area Number 19890062
Research Category

Grant-in-Aid for Young Scientists (Start-up)

Allocation TypeSingle-year Grants
Research Field Pathological medical chemistry
Research InstitutionAkita University (2008)
Tokyo Medical and Dental University (2007)

Principal Investigator

KUBA Keiji  Akita University, 医学部, 准教授 (10451915)

Research Collaborator KIMURA Akinori  東京医科歯科大学, 難治疾患研究所, 教授 (60161551)
Project Period (FY) 2007 – 2008
Project Status Completed (Fiscal Year 2008)
Budget Amount *help
¥3,075,000 (Direct Cost: ¥2,670,000、Indirect Cost: ¥405,000)
Fiscal Year 2008: ¥1,755,000 (Direct Cost: ¥1,350,000、Indirect Cost: ¥405,000)
Fiscal Year 2007: ¥1,320,000 (Direct Cost: ¥1,320,000)
Keywordsアンジオテンシン / ACE2 / Apelin / SARS / ARDS / 急性肺傷害 / 酸化ストレス / Toll-like receptor 4 / 自然免疫 / 酸化リン脂質 / 高病原性インフルエンザ / H5N1
Research Abstract

新規ACE ファミリー分子であるアンジオテンシン変換酵素2(ACE2)はアンジオテンシンII を分解してレニン-アンジオテンシン系を負に調節し、心血管機能の制御などに関与する一方で、SARS(重症急性呼吸器症候群)ウイルスの受容体であるとともに、急性肺傷害において肺保護作用を発揮する。しかしながら、その肺保護作用の分子細胞メカニズムは不明であった。本研究課題において、私たちはACE2 の発現が酸化ストレスにより制御されることを見出し、遺伝子改変マウスを用いた解析からアンジオテンシンを介したマクロファージの活性化が重要であることを明らかにした。さらに酸化ストレスによる酸化リン脂質の産生を介した自然免疫シグナルの過剰な活性化が、SARS のみならず高病原性H5N1 インフルエンザによるARDS/急性肺傷害の病態発症に重要であることを見出した。実際にSARS などに加えて幅広い原因によるARDS/急性肺傷害の患者検体の肺病理組織においても酸化リン脂質の産生が認められた(Cell, 2008)。これらの成果は、SARS、急性肺傷害の治療のみならず幅広い疾患の病態解明、新しい治療法の開発に貢献することが期待される。

Report

(3 results)
  • 2008 Annual Research Report   Final Research Report ( PDF )
  • 2007 Annual Research Report
  • Research Products

    (32 results)

All 2009 2008 2007 Other

All Journal Article (14 results) (of which Peer Reviewed: 12 results) Presentation (17 results) Book (1 results)

  • [Journal Article] Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations2009

    • Author(s)
      Camargo S, Kuba K, et.al.
    • Journal Title

      Gastroenterology 136(3)

      Pages: 872-882

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The role of ACE2 in pulmonary diseases--relevance for the nephrologist2009

    • Author(s)
      Oudit GY, Kuba K, et.al.
    • Journal Title

      Nephrol Dial Transplant 24(5)

      Pages: 1362-1365

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Tissue-specificamino acid transporter partners ACE2 and Collectrin differentially interact with Hartnupmutations2008

    • Author(s)
      Camargo SM, Kuba K, et.al.
    • Journal Title

      Gastroenterology

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Thediscovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice2008

    • Author(s)
      Imai Y, Kuba K, Penninger JM
    • Journal Title

      ExpPhysiol 93(5)

      Pages: 543-8

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Identification ofoxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury2008

    • Author(s)
      Imai Y, Kuba K, et.al.
    • Journal Title

      Cell 133(2)

      Pages: 235-49

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] The discoveryof ACE2 and its role in acute lung injury2008

    • Author(s)
      Penninger J, Imai Y, Kuba K
    • Journal Title

      ExpPhysiol

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Lessonsfrom SARS a new potential therapy for acuterespiratory distress syndrome (ARDS) withangiotensin converting enzyme 2 (ACE2)]2008

    • Author(s)
      Imai Y, Kuba K, Penninger JM
    • Journal Title

      Masui 57(3)

      Pages: 302-10

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] ACE2の疾患病態発症における役割2008

    • Author(s)
      久場敬司、今井由美子、木村彰方
    • Journal Title

      医学のあゆみ Vol.226, No.11

    • Related Report
      2008 Final Research Report
  • [Journal Article] Toll様受容体4-TRIFを介した過剰免疫はH5N1インフルエンザウイルスによる呼吸不全を重症化させる2008

    • Author(s)
      今井由美子、久場敬司、Penninger JM.
    • Journal Title

      細胞工学 27(7)

      Pages: 696-97

    • Related Report
      2008 Final Research Report
  • [Journal Article] Identification of oxidative stress and toll like receptor 4 signaling as a key pathway of acute lung injury2008

    • Author(s)
      Imai Y, Kuba K, et.al.
    • Journal Title

      Cell 18 ; 133(2)

      Pages: 235-249

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impaired heartcontractility in Apelin gene-deficient miceassociated with aging and pressure overload2007

    • Author(s)
      Kuba K, Kimura A, et.al.
    • Journal Title

      Circ Res 101(4)

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Angiotensin-converting enzyme 2 in acuterespiratory distress syndromeal.2007

    • Author(s)
      Imai Y, Kuba K, Penninger JM
    • Journal Title

      Cell Mol Life Sci 64(15)

      Pages: 2006-12

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload2007

    • Author(s)
      Kuba K, et. al.(30著者、1番目)
    • Journal Title

      Circulation Research 101(4)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Renin angiotensin system and acute respiratory distress syndrome (ARDS)2007

    • Author(s)
      Imai Y, Kuba K, Penninger JM
    • Journal Title

      Drug Discovery Today 3

      Pages: 225-229

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] アンジオテンシン変換酵素2(ACE2)によるARDS/急性肺傷害阻止のメカニズム2008

    • Author(s)
      久場敬司
    • Organizer
      第9回東京アンジオテンシン研究会
    • Place of Presentation
      東京(経団連会館)
    • Year and Date
      2008-12-13
    • Related Report
      2008 Final Research Report
  • [Presentation] 11th Cardiovascular Genomicsand Atherosclerosis Symposium2008

    • Author(s)
      久場敬司
    • Organizer
      Angiotensin converting enzyme 2 and itsnew substrate Apelin in heart diseases
    • Place of Presentation
      Seoul, Korea
    • Year and Date
      2008-11-01
    • Related Report
      2008 Final Research Report
  • [Presentation] アンジオテンシン変換酵素(ACE2)と心血管機能制御2008

    • Author(s)
      久場敬司
    • Organizer
      第12回Molecular Cardiocvascular conference
    • Place of Presentation
      北海道、キロロ
    • Year and Date
      2008-09-05
    • Related Report
      2008 Annual Research Report
  • [Presentation] 新規生理活性物質アペリン遺伝子欠損マウスの心筋梗塞モデルにおける心機能障害の研究2008

    • Author(s)
      久場敬司
    • Organizer
      第13回アディポサイエンス研究会シンポジウム
    • Place of Presentation
      大阪
    • Year and Date
      2008-08-22
    • Related Report
      2008 Final Research Report
  • [Presentation] 夏の研修旅行 : 研究三都物語、大阪、トロント、ウィーン2008

    • Author(s)
      久場敬司
    • Organizer
      深水昭吉研究室
    • Place of Presentation
      和光純薬湯河原研修所、大会議室
    • Year and Date
      2008-07-27
    • Related Report
      2008 Final Research Report
  • [Presentation] アンジオテンシン変換酵素2(ACE2)の疾患病態発症における役割2008

    • Author(s)
      久場敬司
    • Organizer
      第6回宮崎生活習慣病研究会
    • Place of Presentation
      宮崎観光ホテル、3階「緋耀の間」
    • Year and Date
      2008-06-06
    • Related Report
      2008 Final Research Report
  • [Presentation] 急性肺傷害の炎症におけるSARSレセプターACE2の役割2008

    • Author(s)
      久場敬司
    • Organizer
      メタボリックリサーチフォーラム
    • Place of Presentation
      東京
    • Year and Date
      2008-03-15
    • Related Report
      2008 Final Research Report
  • [Presentation] Angiotensin converting enzyme 2 and itsnew substrate, Apelin2008

    • Author(s)
      久場敬司
    • Organizer
      MTT International Symposium
    • Place of Presentation
      東京医科歯科大学、難治疾患研究所1階会議室
    • Year and Date
      2008-03-07
    • Related Report
      2008 Final Research Report
  • [Presentation] 疾患病態発症におけるACE2(アンジオテンシン変換酵素2)の役割2008

    • Author(s)
      久場敬司
    • Organizer
      第4回宮崎サイエンスキャンプ
    • Place of Presentation
      ワールドコンベンションセンターサミット・宮崎
    • Year and Date
      2008-02-15
    • Related Report
      2008 Final Research Report
  • [Presentation] アンジオテンシン変換酵素(ACE2)と心血管機能制御2008

    • Author(s)
      久場敬司
    • Organizer
      第12回MolecularCardiocvascular conference
    • Place of Presentation
      北海道キロロ、ホテルピアノ2階「キロロボールルーム・大」
    • Related Report
      2008 Final Research Report
  • [Presentation] 心機能維持におけるACE2の役割2007

    • Author(s)
      久場敬司
    • Organizer
      第8回アンジオテンシン研究会
    • Place of Presentation
      東京、経団連会館ビル
    • Year and Date
      2007-12-08
    • Related Report
      2008 Final Research Report
  • [Presentation] SARSレセプターACE2によるARDS治療2007

    • Author(s)
      久場敬司
    • Organizer
      第38回血管研究会
    • Place of Presentation
      東京
    • Year and Date
      2007-11-22
    • Related Report
      2008 Final Research Report
  • [Presentation] Endogenous Apelin maintains heart contractility in aging and pressure overload2007

    • Author(s)
      Kuba K, et. al.
    • Organizer
      American Heart Association Scientific Session
    • Place of Presentation
      Orlando, USA
    • Year and Date
      2007-11-07
    • Related Report
      2007 Annual Research Report
  • [Presentation] A critical role of Angiotensin converting enzyme 2 (ACE2) in severe acute lung injury2007

    • Author(s)
      Kuba K, Imai Y, Uhlig S, Slutsky A, Penninger JM
    • Organizer
      American Thoracic Society International Conference
    • Place of Presentation
      San Francisco, USA
    • Year and Date
      2007-05-21
    • Related Report
      2007 Annual Research Report
  • [Presentation] Endogenous Apelin maintains heartcontractility in aging and pressureoverload2007

    • Author(s)
      久場敬司
    • Organizer
      AHA Scientific Session 2007
    • Place of Presentation
      米国オーランド
    • Related Report
      2008 Final Research Report
  • [Presentation] Apelin playsa crucial role in maintaining heartcontractility in aging and pressureoverload2007

    • Author(s)
      久場敬司
    • Organizer
      第11回MolecularCardiocvascular Conference
    • Place of Presentation
      北海道キロロ
    • Related Report
      2008 Final Research Report
  • [Presentation] A critical role of Angiotensinconverting enzyme 2(ACE2)in severe acutelung injury2007

    • Author(s)
      久場敬司
    • Organizer
      ATS International Conference2007
    • Place of Presentation
      米国サンフランシスコ
    • Related Report
      2008 Final Research Report
  • [Book] Encyclopedia ofMolecular Mechanisms of Disease edited byFlorian Lang, Tubingen

    • Author(s)
      Kuba K, Imai Y, Penninger JM
    • Publisher
      Severe acuterespiratory distress syndrome(in press)
    • Related Report
      2008 Final Research Report

URL: 

Published: 2007-04-01   Modified: 2016-04-21  

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