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New target and therapeutic approach to influenza virus-induced multiple organ failure

Research Project

Project/Area Number 23791180
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Pediatrics
Research InstitutionThe University of Tokushima

Principal Investigator

CHIDA Junji  徳島大学, 疾患酵素学研究センター, 助教 (20437651)

Project Period (FY) 2011 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsインフルエンザ脳症(IAE) / 多臓器不全(MOF) / ミトコンドリア / 脂肪酸代謝不全 / アデノシン三リン酸(ATP) / サイトカイン / インフルエンザ / 脳症 / 多臓器不全 (MOF) / 脂肪酸代謝 / アデノシン三リン酸 (ATP) / 分子生物学 / 多臓器不全 / アデノシン三リン酸
Research Abstract

Severe influenza including influenza-associated encephalopathy (IAE) is characterized by cytokine storm and multi-organ failure (MOF) with severe edema. However, the relationship amongst factors, such as cytokine storm, hyper-vascular permeability, and metabolic d i s o r d e r s , remain unclear. We generated gene targeted mouse models of the CPT2 variants, analyzed ATP levels in various organs of severe influenza, and found significant ATP depletion after virus infection. We conclude that ATP depletion in various organs elicited sudden-onset of brain edema and MOF in associated with influenza virus-cytokine-protease cycle. To address this problem, we have established a clinically applicable drugs and diagnostic assessment strategy.

Report

(3 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Research-status Report
  • Research Products

    (46 results)

All 2013 2012 2011 2010 2008 Other

All Journal Article (23 results) (of which Peer Reviewed: 20 results,  Open Access: 1 results) Presentation (19 results) Patent(Industrial Property Rights) (4 results) (of which Overseas: 3 results)

  • [Journal Article] Blood lactate/ATP score (A-LES) as a real-time diagnostic/prognostic biomarker of patients in critical care2013

    • Author(s)
      Chida J, et al. (他 9 名)
    • Journal Title

      PloS One

      Volume: 8 (4)

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Extraction and quantification of adenosine triphosphate in mammalian tissues and cells2013

    • Author(s)
      Chida J
    • Journal Title

      International review of cytology

      Volume: in press

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Blood lactate/ATP ratio, as an alarm index and real-time biomarker in critical illness.2013

    • Author(s)
      Junji Chida
    • Journal Title

      PLoS One

      Volume: 8(4) Issue: 4 Pages: e60561-e60561

    • DOI

      10.1371/journal.pone.0060561

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oral clarithromycin enhances airway immunoglobulin A (IgA) immunity through induction of IgA class switching recombination and B-cell-activating factor of the tumor necrosis factor familymolecule on mucosal dendritic cells in mice infected with influenza A virus.2012

    • Author(s)
      Takahashi E, et al. (他 8 名)
    • Journal Title

      Journal of virology

      Volume: 86 (20)4 Pages: 10924-10934

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] An efficient extraction method for quantitation of adenosine triphosphate in mammalian tissues and cells2012

    • Author(s)
      Chida J, et al.
    • Journal Title

      Analytica chimica acta

      Volume: 727 Pages: 8-12

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure2012

    • Author(s)
      Kido H, et al.
    • Journal Title

      Biochimica et Biophysica acta

      Volume: 1824 (1) Pages: 186-194

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children2012

    • Author(s)
      Kubota M, et al. (他 12 名)
    • Journal Title

      Brain and development

      Volume: 34 (1) Pages: 20-27

    • Related Report
      2012 Annual Research Report 2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] インフルエンザ脳症の発症機序 -CPT2 遺伝子多型が解き明かす発症リスク-2012

    • Author(s)
      木戸 博, et al. (他 1 名)
    • Journal Title

      医学のあゆみ

      Volume: 241 (1) Pages: 23-28

    • Related Report
      2012 Annual Research Report 2012 Final Research Report
  • [Journal Article] Oral clarithromycin enhances airway immunoglobulin A (IgA) immunity through induction of IgA class switching recombination and B-cell-activating factor of the tumor necrosis factor family molecule on mucosal dendritic cells in mice infected with influenza A virus2012

    • Author(s)
      Takahashi E
    • Journal Title

      Journal of virology

      Volume: 86 (20) Pages: 10924-10934

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An efficient extraction method for quantitation of adenosine triphosphate in mammalian tissues and cells2012

    • Author(s)
      J Chida
    • Journal Title

      Anal Chim Acta

      Volume: (In press) Pages: 8-12

    • DOI

      10.1016/j.aca.2012.03.022

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An efficient method for extraction from tissues and cells for quantitation of ATP levels2012

    • Author(s)
      Chida J, et al.
    • Journal Title

      Analytical chimica acta

      Volume: -

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] インフルエンザ脳症の発症機序 -CPT2 遺伝子多型が解き明かす発症リスク-2012

    • Author(s)
      Kido H, et al.
    • Journal Title

      医学のあゆみ

      Volume: 241 (1) Pages: 189-194

    • Related Report
      2011 Research-status Report
  • [Journal Article] Role of host cellular protease in pathogenesis of influenza and influenza-induced multiple organ failure2012

    • Author(s)
      Kido H, et al.
    • Journal Title

      Biochimica et biophysica acta

      Volume: 1824 (1) Pages: 189-194

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Thermolabaile CPT2 variants and low blood ATP levels closely related to severity of acute encephalopathy in Japanese children2012

    • Author(s)
      Kubota M, et al.
    • Journal Title

      Brain and development

      Volume: 34 (1) Pages: 20-27

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Bezafibrate up-regulates carnitine palmitoyltransferase 2 expression and promotes mitochondrial energy crisis dissipation in fibroblasts of patients with influenza associated encephalopathy2011

    • Author(s)
      Yao M, et al. (他 5 名)
    • Journal Title

      Molecular genetics and metabolism

      Volume: 104 (3) Pages: 265-272

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Influenza virus-cytokine-protease cycle are principal mechanisms of multi-organ failure in severe influenza and therapeutic approaches2011

    • Author(s)
      Chida J, et al. (他 4 名)
    • Journal Title

      Other Respi Viruses

      Volume: 5 (1) Pages: 281-286

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Characterization of compound missense mutation and deletion of carnitine palmitoyltransferase 2 in a patient with adenovirus-associated encephalopathy2011

    • Author(s)
      Yao M, et al. (他 5 名)
    • Journal Title

      The journal of medical invistigation

      Volume: 58 (3-4) Pages: 210-218

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] 熱中症の新しいリスクファクターとしての熱不安定性フェノタイプ症2011

    • Author(s)
      織田 順, et al. (他 6 名)
    • Journal Title

      日本救急医学会雑誌

      Volume: 22 (7) Pages: 350-351

    • Related Report
      2012 Final Research Report 2011 Research-status Report
  • [Journal Article] Up-regulation of ectopic trypsin in myocardium by influenza A virus infection triggers acute myocarditis2011

    • Author(s)
      Pan H, et al. (他 6 名)
    • Journal Title

      Cardiovascular research

      Volume: 89 (3) Pages: 595-603

    • Related Report
      2012 Final Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure2011

    • Author(s)
      Kido H, Okumura Y, Takahashi E., et al
    • Journal Title

      Biochim Biophys Acta

      Volume: 1824(1) Issue: 1 Pages: 186-194

    • DOI

      10.1016/j.bbapap.2011.07.001

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bezafibrate up-regulates carnitine palmitoyltransferase 2 expression and promotes mitochondrial energy crisis dissipation in fibroblasts of patients with influenza-associated encephalopathy2011

    • Author(s)
      Yao M, et al.
    • Journal Title

      Molecular genetics and metabolise

      Volume: 104 (3) Pages: 265-272

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Characterization of compound missense mutation and deletion of carnitine palmitoyltransferase 2 (CPT2) in a patient with adenovirus-associated encephalopathy2011

    • Author(s)
      Yao M, et al.
    • Journal Title

      The journal of medical investigation

      Volume: 58 (3-4) Pages: 210-218

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Extraction and quantification of ATP (adenosine triphosphate) in mammalian tissues and cells

    • Author(s)
      Chida J, et al. (他 1 名)
    • Journal Title

      International review of cytology

      Volume: (in press)

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Presentation] New target and therapeutic approach to influenza virus induced multiple organ failure: effects of diisopropylamine dichloroacetate on energy crisis rescue2012

    • Author(s)
      山根 一彦, et al.
    • Organizer
      第85回 日本生化学会大会
    • Place of Presentation
      福岡国際会議場/マリンメッセ福岡 (福岡県)
    • Year and Date
      2012-12-15
    • Related Report
      2012 Final Research Report
  • [Presentation] ICU 入室患者における末梢血アデノシン三リン酸と転帰との関係2012

    • Author(s)
      小野寺 睦雄, et al.
    • Organizer
      第39回 日本集中治療医学会学術集会
    • Place of Presentation
      幕張メッセ (千葉県)
    • Year and Date
      2012-02-28
    • Related Report
      2012 Final Research Report
  • [Presentation] Up-regulations of ectopic trypsins and MMP-9 by influenza virus infection triggers MOF and therapeutic approaches2011

    • Author(s)
      Chida J, et al.
    • Organizer
      7th International of proteolysis society
    • Place of Presentation
      Hilton San Diego Resort and Spa (米国)
    • Year and Date
      2011-10-18
    • Related Report
      2012 Final Research Report
  • [Presentation] Trypsin knock down and trypsin inhibitor administration suppressed influenza viral replication and virus-induced myocarditis in the hearts and cardiomyoblast cells2011

    • Author(s)
      Takahashi E, et al.
    • Organizer
      7th International of proteolysis society
    • Place of Presentation
      Hilton San Diego Resort and Spa (米国)
    • Year and Date
      2011-10-18
    • Related Report
      2012 Final Research Report
  • [Presentation] Influenza virus-cytokine-protease cycle and mitochondrial ATP depletion are principal risk factors of multi-organ failure (MOF) and influenza-associated encephalopathy of patients with severe influenza2011

    • Author(s)
      Chida J, et al.
    • Organizer
      International union of microbiological societies 2011 congress
    • Place of Presentation
      札幌コンベンションセンター (北海道)
    • Year and Date
      2011-10-13
    • Related Report
      2012 Final Research Report
  • [Presentation] Pathogenesis and possible treatment targets of multiple organ failure in high-risk patients with severe influenza and animal models2011

    • Author(s)
      Kido H, et al.
    • Organizer
      International union of microbiological societies 2011 congress
    • Place of Presentation
      札幌コンベンションセンター (北海道)
    • Year and Date
      2011-10-13
    • Related Report
      2012 Final Research Report
  • [Presentation] Principal mechanisms of multi-organ failure in severe influenza and therapeutic approaches2011

    • Author(s)
      千田 淳司, et al.
    • Organizer
      第84回 日本生化学会大会
    • Place of Presentation
      国立京都国際会館 (京都府)
    • Year and Date
      2011-09-23
    • Related Report
      2012 Final Research Report
  • [Presentation] インフルエンザ感染による重症化と多臓器不全の新治療法の開発: ジクロロ酢酸誘導体による糖代謝改善を基盤としたエネルギー枯渇の回避2011

    • Author(s)
      山根 一彦, et al.
    • Organizer
      第84回 日本生化学会大会
    • Place of Presentation
      国立京都国際会館 (京都府)
    • Year and Date
      2011-09-23
    • Related Report
      2012 Final Research Report
  • [Presentation] New option for the treatment of influenza virus-induced multiple organ failure (MOF): Effect of dichloroacetic acid derivative on mitochondrial energy crisis2011

    • Author(s)
      Yamane K, et al.
    • Organizer
      5th Biennial meeting of society for free radical research-asia, 8th Conference of asian society for mitochondrial research and medicine, 11th Conference of japanese society of mitochondrial research and medicine
    • Place of Presentation
      鹿児島市民文化ホール (鹿児島県)
    • Year and Date
      2011-09-03
    • Related Report
      2012 Final Research Report
  • [Presentation] 重症患者における乳酸値/ATP 比 (A-LES) の有用性2011

    • Author(s)
      小野 理恵, et al.
    • Organizer
      第58回 日本麻酔科学会
    • Place of Presentation
      神戸ポートピアホテル/神戸国際展示場 (兵庫県)
    • Year and Date
      2011-05-20
    • Related Report
      2012 Final Research Report
  • [Presentation] ICU 入室患者における末梢血アデノシン三リン酸と転帰との関係

    • Author(s)
      Onodera M
    • Organizer
      第 39 回 日本集中治療医学会学術集会
    • Place of Presentation
      幕張メッセ (千葉)
    • Related Report
      2011 Research-status Report
  • [Presentation] Up-regulations of ectopic trypsins and MMP-9 by influenza triggers multi-organ failure and therapeutic approaches

    • Author(s)
      Chida J
    • Organizer
      7th International Proteolysis Society
    • Place of Presentation
      Hilton San Diego Resort and Spa (San Diego, CA USA)
    • Related Report
      2011 Research-status Report
  • [Presentation] Trypsin knock down and trypsin inhibitor administration suppressed influenza viral replication and virus-induced myocarditis in the heart and cardiomyoblast cells

    • Author(s)
      Takahashi E
    • Organizer
      7 th International Proteolysis Society
    • Place of Presentation
      Hilton San Diego Resort and Spa (San Diego, CA USA)
    • Related Report
      2011 Research-status Report
  • [Presentation] Principal mechanisms of multi-organ failure in severe influenza and therapeutic approaches

    • Author(s)
      Chida J
    • Organizer
      第 84 回 日本生化学会大会
    • Place of Presentation
      国立京都国際会館 (京都)
    • Related Report
      2011 Research-status Report
  • [Presentation] インフルエンザ感染による重症化と多臓器不全の新治療法の開発: ジクロロ酢酸誘導体による糖代謝改善を基盤としたエネルギー枯渇の回避

    • Author(s)
      Yamane K
    • Organizer
      第 84 回 日本生化学会大会
    • Place of Presentation
      国立京都国際会館 (京都)
    • Related Report
      2011 Research-status Report
  • [Presentation] Influenza virus-cytokine-protease cycle and mitochondrial ATP depletion are principal risk factors of multi-organ failure and influenza-associated encephalopathy of patients with severe influenza

    • Author(s)
      Chida J
    • Organizer
      International Union of Microbiological Societies 2011 Congress
    • Place of Presentation
      Sapporo Convention Center (北海道)
    • Related Report
      2011 Research-status Report
  • [Presentation] Pathogenesis and possible treatment targets of multi organ failure in high-risk patients with severe influenza and animal models

    • Author(s)
      Kido H
    • Organizer
      International Union of Microbiological Societies 2011 Congress(招待講演)
    • Place of Presentation
      Sapporo Convention Center (北海道)
    • Related Report
      2011 Research-status Report
  • [Presentation] New option for the treatment of influenza virus-induced multiple organ failure: Effect of dichloroacetic acid derivative on mitochondrial energy crisis

    • Author(s)
      Yamane K
    • Organizer
      5th Biennial Meeting of Society for Free Radical Research-Asia, 8th Conference of Asian Society for Mitochondrial Research and Medicine, 11th Conference Society of Mitochondrial Research and Medicine
    • Place of Presentation
      Kagoshima Citizens’ Culture Hall (鹿児島)
    • Related Report
      2011 Research-status Report
  • [Presentation] 重症患者における乳酸値/ATP 比 (A-LES) の有用性

    • Author(s)
      Ono R
    • Organizer
      第 58 回 日本麻酔科学会
    • Place of Presentation
      神戸ポートピアホテル・神戸国際展示場 (神戸)
    • Related Report
      2011 Research-status Report
  • [Patent(Industrial Property Rights)] インフルエンザの治療剤2012

    • Inventor(s)
      木戸 博, 他
    • Industrial Property Rights Holder
      第一三共ヘルスケア
    • Industrial Property Number
      2012-015729
    • Filing Date
      2012
    • Related Report
      2011 Research-status Report
  • [Patent(Industrial Property Rights)] インフルエンザの治療剤または予防剤2011

    • Inventor(s)
      木戸 博, 千田 淳司, 塙 雅明, 山本 善一, 井 紀孝, 角田 健司
    • Industrial Property Rights Holder
      国立大学法人徳島大学, 第一三共ヘルスケア株式会社
    • Filing Date
      2011-09-28
    • Related Report
      2012 Final Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 病気の重症度の検査方法2010

    • Inventor(s)
      木戸 博, 西村 匡司, 千田 淳司
    • Industrial Property Rights Holder
      国立大学法人徳島大学
    • Filing Date
      2010-10-04
    • Related Report
      2012 Final Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 動物組織からのヌクレオチドの抽出法2008

    • Inventor(s)
      木戸 博, 千田 淳司
    • Industrial Property Rights Holder
      国立大学法人徳島大学
    • Filing Date
      2008-01-08
    • Related Report
      2012 Final Research Report
    • Overseas

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Published: 2011-08-05   Modified: 2019-07-29  

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