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Elucidation of the molecular mechanisms of influenza-associated encephalopathy due to disorder of ATP generation in mitochondria

Research Project

Project/Area Number 21790992
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeSingle-year Grants
Research Field Pediatrics
Research InstitutionThe University of Tokushima

Principal Investigator

CHIDA Junji  The University of Tokushima, 疾患酵素学研究センター, 助教 (20437651)

Project Period (FY) 2009 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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) / インフルエンザ / 脳症 / 脂肪酸代謝 / サイトカイン / 分子生物学 / MOF(多臓器不全) / 脂肪酸代謝障害 / ATP(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 disorders, 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)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • Research Products

    (43 results)

All 2011 2010 2009 Other

All Journal Article (21 results) (of which Peer Reviewed: 14 results) Presentation (19 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 2 results)

  • [Journal Article] Up-regulation of ectopic trypsin in myocardium by influenza A virus infection triggers acute myocarditis.2011

    • Author(s)
      Pan H, et al.(他6名, 2番目)
    • Journal Title

      Cardiovascular Research 89(3)

      Pages: 595-603

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Influenza virus-cytokine-protease cycle in the pathogenesis of vascular hyper permeability in severe influenza.2011

    • Author(s)
      Wang S, et al.(他7名, 4番目)
    • Journal Title

      The Journal of Infectious Disease 202(7)

      Pages: 991-1001

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Thermolabile CPT II variants and low ATP levels are closely related to severity of acute encephalopathy children2011

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

      Brain Development

      Volume: (In press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of inhibitors of Toll-like receptors, protease-activated receptor-2 signalings and trypsin on influenza A virus replication and up-regulation of cellular factors in cardiomyocytes2011

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

      The Journal of Medical Investigation

      Volume: 58(1-2) Pages: 19-28

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Up-regulation of ectopic trypsin in myocardium by influenza A virus infection triggers acute myocarditis2011

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

      Cardiovascular Research

      Volume: 89(3) Pages: 595-603

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Influenza virus-cytokine-protease cycle in the pathogenesis of vascular hyper-permeability in severe influenza2011

    • Author(s)
      Wang S, et al.
    • Journal Title

      The Journal of Infectious Disease

      Volume: 202(7) Pages: 991-1001

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mechanisms of multi-organ failure in severe influenza.2010

    • Author(s)
      Kido H, et al.(他3名, 2番目)
    • Journal Title

      Nippon Rinsho 68(8)

      Pages: 1565-1573

    • Related Report
      2010 Final Research Report
  • [Journal Article] Mechanisms of matrix metalloprotease-9 up-regulation and tissue destruction in various organs in influenza A virus infection.2010

    • Author(s)
      Wang S, et al.(他6名, 3番目)
    • Journal Title

      The Journal of Medical Investigation 57(1-2)

      Pages: 26-34

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] インフルエンザ脳症の発症原因-ミトコンドリア脂肪酸代謝障害と血管内皮細胞の膜透過性の亢進-2010

    • Author(s)
      木戸博, et al.(他4名, 3番目)
    • Journal Title

      最新医学 65(1)

      Pages: 52-60

    • Related Report
      2010 Final Research Report
  • [Journal Article] Mechanisms of multi-organ failure in severe influenza2010

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

      Nippon Rinsho

      Volume: 68(8) Pages: 1565-1573

    • Related Report
      2010 Annual Research Report
  • [Journal Article] Mechanisms of matrix metalloprotease-9 up-regulation and tissue destruction in various organs in influenza A virus infection2010

    • Author(s)
      Wang S, et al.
    • Journal Title

      The Journal of Medical Investigation

      Volume: 57(1-2) Pages: 26-34

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] インフルエンザ脳症の発症原因-ミトコンドリア脂肪酸代謝障害と血管内皮細胞の膜透過性の亢進-2010

    • Author(s)
      木戸博, 他
    • Journal Title

      最新医学

      Volume: 65(1) Pages: 52-60

    • Related Report
      2010 Annual Research Report
  • [Journal Article] インフルエンザ脳症の発症原因-ミトコンドリア脂肪酸代謝障害と血管内皮細胞の膜透過性の亢進-2010

    • Author(s)
      木戸博
    • Journal Title

      最新医学 65(1)

      Pages: 52-60

    • Related Report
      2009 Annual Research Report
  • [Journal Article] Mechanisms of matrix metalloprotease-9 up-regulation and tissue in various organs in influenza A virus infection2010

    • Author(s)
      Wang S
    • Journal Title

      The Journal of Medical Investigation 57(1-2)

      Pages: 26-34

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Host envelope glycoprotein processing proteases are indispensable for entry into human cells by seasonal and highly pathogenic avian influenza viruses.2009

    • Author(s)
      Kido H, et al.(他7名, 6番目)
    • Journal Title

      Journal of Molecular Pathogenic and Genetic Medicine 3(1)

      Pages: 167-175

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Boost of mucosal secretory IgA response by clarithromycin (CAM) in paediatric influenza.2009

    • Author(s)
      Sawabuchi T, et al.(他8名, 8番目)
    • Journal Title

      Respirology 14(8)

      Pages: 1173-1179

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] インフルエンザの重症化をめぐって-イン フルエンザ脳症発症の機序の解明-2009

    • Author(s)
      Chida J, et al.(他4名, 1番目)
    • Journal Title

      Antibiotics and Chemotherapy 23

      Pages: 101-109

    • Related Report
      2010 Final Research Report
  • [Journal Article] Boost of mucosal secretory immunoglobulin A response by clarithromycin in paediatric influenza2009

    • Author(s)
      Sawabuchi T
    • Journal Title

      Respirology 14(8)

      Pages: 1173-1179

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] インフルエンザ脳症発症の機序の解明2009

    • Author(s)
      千田淳司
    • Journal Title

      The Japanese Journal of Antibiotics 62

      Pages: 74-77

    • Related Report
      2009 Annual Research Report
  • [Journal Article] Thermolabile CPT II variants and low ATP levels are closely related to severity of acute encephalopathy children.

    • Author(s)
      Kubota M, et al.(他12名, 2番目)
    • Journal Title

      Brain Development In press

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Influenza virus-cytokine-protease cycle are principal mechanisms of multi-organ failure in severe influenza and therapeutic approaches.

    • Author(s)
      Chida J, et al.(他3名, 1番目)
    • Journal Title

      Influenza and Other Respiratory Viruses In press

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Presentation] Effect of Bezafibrate on mitochondrial energy crisis in the fibroblast of severe influenza -associated encephalopathy patients.2010

    • Author(s)
      Yao M, et al.
    • Organizer
      第33回日本分子生物学会年会・第83回日本生化学学会大会合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2010-12-10
    • Related Report
      2010 Final Research Report
  • [Presentation] Effect of Bezafibrate on mitochondrial energy crisis in the fibroblast of severe influenza-associated encephalopathy patients2010

    • Author(s)
      Yao M, et al.
    • 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
      神戸ポートアイランド(神戸市)
    • Year and Date
      2010-12-10
    • Related Report
      2010 Annual Research Report
  • [Presentation] Pathogenesis of impaired systemic energy metabolism by severe influenza virus infection -Analysis using mouse models of defect in mitochondrial β -oxidation of long fatty acids-.2010

    • Author(s)
      Chida J, et al.
    • Organizer
      第33回日本分子生物学会年会・第83回日本生化学学会大会合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2010-12-09
    • Related Report
      2010 Final Research Report
  • [Presentation] Pathogenesis of impaired systemic energy metabohsm by severe influenza virus infection-Analysis using mouse models of defect in mitochondrial β-oxidation of long fatty acids-2010

    • Author(s)
      千田淳司, 他
    • 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
      神戸ポートアイランド(神戸市)
    • Year and Date
      2010-12-09
    • Related Report
      2010 Annual Research Report
  • [Presentation] Influenza virus-cytokine- protease cycle in the pathogenesis of vascular hyper-permeability in severe influenza and its possible treatment.2010

    • Author(s)
      Kido H, et al.
    • Organizer
      第33回日本分子生物学会年会・第83回日本生化学学会大会合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2010-12-08
    • Related Report
      2010 Final Research Report
  • [Presentation] Influenza-cytokine-protease cycle in the pathogenesis of vascular hyper-permeability in severe influenza and its possible treatment2010

    • Author(s)
      木戸博, 他
    • 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
      神戸ポートアイランド(神戸市)
    • Year and Date
      2010-12-08
    • Related Report
      2010 Annual Research Report
  • [Presentation] インフルエンザ脳症の発症メカニズムの酵素学的な解析-ウイルス罹患後に高熱で誘発されるミトコンドリア長鎖脂肪酸代謝障害-2010

    • Author(s)
      千田淳司
    • Organizer
      温熱生理研究会
    • Place of Presentation
      名古屋(招聘講演)
    • Year and Date
      2010-09-10
    • Related Report
      2010 Final Research Report
  • [Presentation] インフルエンザ脳症の発症メカニズムの酵素学的な解析-ウイルス罹患後に高熱で誘発されるミトコンドリアの長鎖脂肪酸代謝障害-2010

    • Author(s)
      千田淳司
    • Organizer
      温熱生理研究会
    • Place of Presentation
      岡崎カンファレンスセンター(愛知県岡崎市)(招聘講演)
    • Year and Date
      2010-09-10
    • Related Report
      2010 Annual Research Report
  • [Presentation] Influenza virus-cytokine -protease cycle and mitochondrial ATP depletion are the principal mechanisms of multi-organ failure in severe influenza and therapeutic approaches.2010

    • Author(s)
      Chida J.
    • Organizer
      Options for Control of Influenza VII
    • Place of Presentation
      香港
    • Year and Date
      2010-09-04
    • Related Report
      2010 Final Research Report
  • [Presentation] Influenza virus-cytokine-protease cycle and mitochondrial ATP depletion are the principal mechanisms of multi-organ failure in severe influenza and therapeutic approaches2010

    • Author(s)
      Chida J, et al.
    • Organizer
      Options for the Control of Influenza VII
    • Place of Presentation
      香港コンベンション&エキシビジョン・センター(香港)
    • Year and Date
      2010-09-04
    • Related Report
      2010 Annual Research Report
  • [Presentation] Up-regulation of ectopic trypsin in myocardium triggers acute myocarditis in severe influenza.2010

    • Author(s)
      Pan H, et al.
    • Organizer
      第15回日本病態プロテアーゼ学会
    • Place of Presentation
      大阪
    • Year and Date
      2010-08-21
    • Related Report
      2010 Final Research Report
  • [Presentation] Up-regulation of ectopic trypsin in myocardium triggers acute myocarditis in severe influenza2010

    • Author(s)
      Pan H, et al.
    • Organizer
      第15回日本病態プロテアーゼ学会
    • Place of Presentation
      千里ライフサイエンスセンター(大阪府豊中市)
    • Year and Date
      2010-08-21
    • Related Report
      2010 Annual Research Report
  • [Presentation] Pathogenesis of mitochondrial ATP depletion of mice caused by influenza virus and therapeutic approach for them using DCA drug.2009

    • Author(s)
      Chida J, et al.
    • Organizer
      第82回日本生化学学会大会
    • Place of Presentation
      神戸
    • Year and Date
      2009-10-23
    • Related Report
      2010 Final Research Report
  • [Presentation] Influenza-cytokine- protease cycle in the pathogenesis of cytokine storm in severe influenza.2009

    • Author(s)
      Wang S, et al.
    • Organizer
      第82回日本生化学学会大会
    • Place of Presentation
      神戸
    • Year and Date
      2009-10-23
    • Related Report
      2010 Final Research Report
  • [Presentation] Effect of Beazfibrate on mitochondrial energy crisis in the fibroblasts of severe influenza- associated encephalopathy patients.2009

    • Author(s)
      Yao M, et al.
    • Organizer
      第82回日本生化学学会大会
    • Place of Presentation
      神戸
    • Year and Date
      2009-10-23
    • Related Report
      2010 Final Research Report
  • [Presentation] Host cellular factors and their mechanisms of influenza aggravation, and recent data for the prevention at mucosal surface.2009

    • Author(s)
      Kido H, et al.
    • Organizer
      第82回日本生化学学会大会
    • Place of Presentation
      神戸
    • Year and Date
      2009-10-22
    • Related Report
      2010 Final Research Report
  • [Presentation] Host cellular factors and their mechanisms of influenza aggravation, and recent Data for the prevention at mucosal surface2009

    • Author(s)
      Kido H
    • Organizer
      第82回 日本生化学会大会
    • Place of Presentation
      神戸市
    • Related Report
      2009 Annual Research Report
  • [Presentation] Pathogenesis of mitochondrial ATP depletion of mice caused by influenza virus and therapeutic for them using DCA drug2009

    • Author(s)
      Chida J
    • Organizer
      第82回 日本生化学会大会
    • Place of Presentation
      神戸市
    • Related Report
      2009 Annual Research Report
  • [Presentation] Effect of Bezafibrate on mitochondrial energy crisis in the fibroblasts of severe influenza-associated encephalopathy patients2009

    • Author(s)
      Yao M
    • Organizer
      第82回 日本生化学会大会
    • Place of Presentation
      神戸市
    • Related Report
      2009 Annual Research Report
  • [Patent(Industrial Property Rights)] 病気の重症度の検査法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
      2010 Final Research Report
  • [Patent(Industrial Property Rights)] 病気の重症度の検査法2010

    • Inventor(s)
      千田淳司, 他
    • Industrial Property Rights Holder
      国立大学法人徳島大学
    • Filing Date
      2010-10-04
    • Related Report
      2010 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] ヌクレオチドの抽出方法2009

    • Inventor(s)
      千田淳司
    • Industrial Property Rights Holder
      国立大学法人徳島大学
    • Filing Date
      2009-03-29
    • Related Report
      2009 Annual Research Report
    • Overseas

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Published: 2009-04-01   Modified: 2016-04-21  

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