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Research on the interaction of histones in pathophysiology of sepsis and its application

Research Project

Project/Area Number 18H02906
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 55060:Emergency medicine-related
Research InstitutionOsaka Institute of Technology

Principal Investigator

Kawahara Ko-ichi  大阪工業大学, 工学部, 教授 (10381170)

Co-Investigator(Kenkyū-buntansha) 丸山 征郎  鹿児島大学, 医歯学総合研究科, 特任教授 (20082282)
今泉 均  東京医科大学, 医学部, 教授 (70203304)
伊藤 隆史  鹿児島大学, 医歯学総合研究科, 特任准教授 (20381171)
三浦 直樹  鹿児島大学, 農水産獣医学域獣医学系, 教授 (80508036)
中島 利博  東京医科大学, 医学部, 教授 (90260752)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Keywords敗血症 / DAMPs / ヒストン
Outline of Final Research Achievements

Recently, histone H3 and H4, are released into the extracellular space during sepsis and act as major mediators of death of an organism and induce platelet activation, suggesting that the extracellular histones may be damage-associated molecular patterns (DAMPs). However, histone H2A and H2B still remain unclear. In this study, the results showed that both histone H2A and H2B significantly induced the release of TNF-α in RAW264.7 cells. Histone H2A and H2B activated ERK1/2, p38MAPK and JNK, respectively. Furthermore, U0126, the inhibitor of ERK1/2 activation, significantly inhibited TNF-α induction by histone H2A and H2B in RAW264.7 cells, but not p38MAPK inhibitor SB203580 and JNK inhibitor SP600125. Therefore, our findings suggest that in the extracellular milieu, the role of Histone H2A and H2B might induce TNF-α via ERK1/2 activation in the tissue-damaged diseases such as sepsis and rheumatoid arthritis.

Academic Significance and Societal Importance of the Research Achievements

敗血症の定義が「生命を脅かす臓器障害」と改定された。これはDAMPsの重要性が示唆される。DAMPsとは臓器障害の細胞から放出され、個体死へと導く分子である。最近、ヒストンが新規DAMPsと示された。ヒストンH3、H4が細胞傷害、血小板凝集を惹起するからである。本研究成果では、ヒストンH2A、H2BがDAMPsとして証明された。すなわち、ヒストンのDAMPsとしての機能が解明された。よって、ヒストンにはそれぞれ役割があることが示唆され、新規の治療法の確立につながると確信した。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(9 results)

All 2021 2020 2019 2018

All Journal Article (5 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (4 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Protective effects of recombinant human soluble thrombomodulin on ischemia reperfusion injury of spinal cord in rabbits2021

    • Author(s)
      Imagama I, Kawahara K, Ueno H, Maruyama I, Imoto H
    • Journal Title

      Medical Journal of Kagoshima University

      Volume: 73 Pages: 16-22

    • NAID

      120007001538

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adsorptive granulocyte and monocyte apheresis: A potentially relevant therapeutic option for COVID-192020

    • Author(s)
      Kanekura Takuro、Kawahara Koichi
    • Journal Title

      International Journal of Infectious Diseases

      Volume: 99 Pages: 1-2

    • DOI

      10.1016/j.ijid.2020.07.025

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TLR4/MD-2 is a receptor for extracellular nucleophosmin 12020

    • Author(s)
      Nakatomi Kota、Ueno Hikari、Ishikawa Yuto、Salim Ronny、Mori Yuki、Kanemoto Issey、Tancharoen Salunya、Kikuchi Kiyoshi、Miura Naoki、Omori Taketo、Okuda?ashitaka Emiko、Matsumura Kiyoshi、Imaizumi Hitoshi、Motomiya Yoshihiro、Maruyama Ikuro、Kawahara Ko-Ichi
    • Journal Title

      Biomedical Reports

      Volume: 14 Pages: 1-6

    • DOI

      10.3892/br.2020.1397

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Uric acid enhances alteplase-mediated thrombolysis as an antioxidant.2018

    • Author(s)
      Kikuchi K, Setoyama K, Tanaka E, Otsuka S, Terashi T,Nakanishi K, Takada S, Sakakima H, Ampawong S, Kawahara KI, Nagasato T, Hosokawa K, Harada Y, YamamotoM, Kamikokuryo C, Kiyama R, Morioka M, Ito T, Maruyama I, Tancharoen S.
    • Journal Title

      Scientific Reports

      Volume: 8(1) Pages: 1-12

    • DOI

      10.1038/s41598-018-34220-1

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Application of a Novel Anti-Adhesive Membrane, E8002, in a Rat Laminectomy Model.2018

    • Author(s)
      Kikuchi K, Setoyama K, Terashi T, Sumizono M, Tancharoen S, Otsuka S, Takada S, Nakanishi K, Ueda K, Sakakima H, Kawahara KI, Maruyama I, Hattori G, Morioka M, Tanaka E, Uchikado H.
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 19(5) Pages: 1-9

    • DOI

      10.3390/ijms19051513

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] ヒストンH2AとH2BはMD2/ERK1/2を介してTNF-αを誘導する2020

    • Author(s)
      上野 光理, Ronny Christiadi Salim, 石濱 一貴, 朝田 成重, 山下 侑子, Tancharoen Salunya, 菊池 清志, 伊藤 隆史, 丸山 征郎, 川原 幸一
    • Organizer
      第42回日本血栓止血学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 細胞外Nucleophosminの受容体は TLR-4である2020

    • Author(s)
      中富康太, 董建暉, 金本一誠, Ronny Christiadi Salim, 上野光理, Salunya Tancharoen, 菊池清志 伊藤隆史, 丸山征郎, 川原幸一
    • Organizer
      日本薬学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] TNF-a induction by Histone H2A and H2B is mediated via ERK1/2 in RAW264.7 cells.2019

    • Author(s)
      Hikari Ueno, Kota Nakatomi, Shuto Anan, Salunya Tancharoen, Kiyoshi Kikuchi, Takashi Ito, Ikuro Maruyama, Ko-ichi Kawahara
    • Organizer
      International DAMPs and Alarmins Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The extracellular Nucleophosmin Receptor is TLR-42019

    • Author(s)
      Kota Nakatomi, Ronny Christiadi Salim, Issey Kanemoto, Hikari Ueno, Dong Jianhui, Salunya Tancharoen, Kiyoshi Kikuchi, Takashi Ito, Ikuro Maruyama, Ko-ichi Kawahara.
    • Organizer
      International DAMPs and Alarmins Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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