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Suppression of delayed ROS rescue normal human fibroblasts after radiation exposure.

Research Project

Project/Area Number 19K08150
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52040:Radiological sciences-related
Research InstitutionNara Medical University

Principal Investigator

KOBASHIGAWA SHINKO  奈良県立医科大学, 医学部, 研究員 (70637628)

Co-Investigator(Kenkyū-buntansha) 菓子野 元郎  奈良県立医科大学, 医学部, 准教授 (00437287)
森 英一朗  奈良県立医科大学, 医学部, 准教授 (70803659)
Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Discontinued (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords放射線治療 / 遅発性活性酸素種 / 炎症 / 細胞老化 / ミトコンドリア / 防護 / SASP / 放射線 / ATM / アスコルビン酸誘導体 / 電離放射線 / 正常細胞の防護
Outline of Research at the Start

我々は放射線照射細胞において、ミトコンドリアの異常から生じる「遅発性活性酸素種」が照射3~5日後に爆発的に生じることを見出している。さらに「正常細胞では、遅発性活性酸素が放射線による細胞老化に関わる」ことを明らかにした。近年、老化細胞からの分泌物(SASP因子)によって炎症が引き起こされることが考えられるようになってきた。このことから、「遅発性活性酸素種が細胞老化を介して、照射後の正常組織において遅発性の炎症を引き起こしている」可能性が考えられる。そこで遅発性活性酸素種を抑制することにより、放射線治療効果を落とすことなく、正常組織の炎症軽減が可能か検証する。

Outline of Final Research Achievements

The aim of this study was to clarify the difference in response to delayed reactive oxygen species between cancer cells and normal cells, and to verify the protective effect of normal tissues by targeting delayed reactive oxygen species after radiation exposure.
The difference between cancer cells and normal cells was that when normal cells are irradiated with a high dose (6 Gy) of X-rays, delayed reactive oxygen species are maintained at a high level even 7 days after irradiation, whereas in cancer cells was to return to the level of non-irradiated cells 7 days after irradiation. As a result of examining cellular senescence-related proteins, suppression of delayed reactive oxygen species by antioxidant (AA-2G) decreased the phosphorylation level of ATM and the activation of p53 after 5 days after irradiation. Delayed reactive oxygen species were suggested to maintain the activation of ATM by oxidization.

Academic Significance and Societal Importance of the Research Achievements

遅発性活性酸素種の抑制によって放射線による細胞老化の頻度を減少させ、ある程度正常細胞の生存率を改善させることが可能であることがわかった。よって、抗酸化剤の持続的な投与によって、治療効果を落とすことなく、放射線治療による正常組織への影響を軽減できる可能性が示唆された。しかしながら、放射線治療の課題である炎症の軽減については、老化関連分泌因子の発現に影響しないことから、遅発性活性酸素種の制御では困難であることがわかった。よって、放射線治療による炎症性メディエータレベルの増加については、抗酸化剤投与とは別にSenolytic drug投与による老化細胞除去が必要であると考えている。

Report

(4 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (18 results)

All 2022 2021 2020 2019 Other

All Journal Article (11 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 9 results,  Open Access: 11 results) Presentation (6 results) (of which Int'l Joint Research: 2 results) Remarks (1 results)

  • [Journal Article] C9orf72-Derived Proline:Arginine Poly-Dipeptides Modulate Cytoskeleton and Mechanical Stress Response2022

    • Author(s)
      Shiota Tomo、Nagata Riko、Kikuchi Sotaro、Nanaura Hitoki、Matsubayashi Masaya、Nakanishi Mari、Kobashigawa Shinko、Isozumi Noriyoshi、Kiriyama Takao、Nagayama Kazuaki、Sugie Kazuma、Yamashiro Yoshito、Mori Eiichiro
    • Journal Title

      Frontiers in Cell and Developmental Biology

      Volume: 10 Pages: 750829-750829

    • DOI

      10.3389/fcell.2022.750829

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 放射線による ATM 活性化機構について2022

    • Author(s)
      小橋川新子、菓子野元郎
    • Journal Title

      放射線生物研究 Radiation Biology Research Communications

      Volume: 57(1) Pages: 50-62

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gene expression profiles of human cerebral organoids identify PPAR pathway and PKM2 as key markers for oxygen-glucose deprivation and reoxygenation2021

    • Author(s)
      Naoki Iwasa, Takeshi K. Matsui, Naohiko Iguchi, Kaoru Kinugawa, Naritaka Morikawa, Yoshihiko M. Sakaguchi, Tomo Shiota, Shinko Kobashigawa et. al.
    • Journal Title

      Frontiers in Cellular Neuroscience

      Volume: - Pages: 605030-605030

    • DOI

      10.3389/fncel.2021.605030

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oxygen-glucose deprivation and reoxygenation on human cerebral organoids alters expression related to lipid metabolism2021

    • Author(s)
      Iwasa Naoki、Matsui Takeshi K.、Morikawa Naritaka、Sakaguchi Yoshihiko M.、Shiota Tomo、Iguchi Naohiko、Nishimura Yuhei、Mori Eiichiro、Sugie Kazuma
    • Journal Title

      Frontiers in Neuroscience

      Volume: -

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Brainstem organoids from human pluripotent stem cells2020

    • Author(s)
      Nobuyuki Eura, Takeshi K. Matsui, Joachim Luginbuhl, Masaya Matsubayashi, Hitoki Nanaura, Tomo Shiota, Kaoru Kinugawa, Naohiko Iguchi, Takao Kiriyama, Canbin Zheng, Tsukasa Kouno, Yan Jun Lan, Pornparn Kongpracha, Pattama Wiriyasermkul, Yoshihiko M. Sakaguchi, Riko Nagata, Tomoya Komeda, Naritaka Morikawa, et al.
    • Journal Title

      Frontiers in Neuroscience

      Volume: - Pages: 00538-00538

    • DOI

      10.3389/fnins.2020.00538

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inhibition of the ATR kinase enhances 5-FU sensitivity independently of nonhomologous end-joining and homologous recombination repair pathways2020

    • Author(s)
      Ito Soichiro S.、Nakagawa Yosuke、Matsubayashi Masaya、Sakaguchi Yoshihiko M.、Kobashigawa Shinko、Matsui Takeshi K.、Nanaura Hitoki、Nakanishi Mari、Kitayoshi Fumika、Kikuchi Sotaro、Kajihara Atsuhisa、Tamaki Shigehiro、Sugie Kazuma、Kashino Genro、Takahashi Akihisa、Hasegawa Masatoshi、Mori Eiichiro、Kirita Tadaaki
    • Journal Title

      Journal of Biological Chemistry

      Volume: 295 Issue: 37 Pages: 12946-12961

    • DOI

      10.1074/jbc.ra120.013726

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 27‐Hydroxycholesterol regulates human SLC22A12 gene expression through estrogen receptor action2020

    • Author(s)
      Matsubayashi M、Sakaguchi YM.、Sahara Y、Nanaura H、Kikuchi S、Asghari A、Bui L、Kobashigawa S、Nakanishi M、Nagata R、Matsui TK.、Kashino G、Hasegawa M、Takasawa S、Eriguchi M、Tsuruya K、Nagamori S、Sugie K、Nakagawa T、Takasato M、Umetani M、Mori E
    • Journal Title

      The FASEB Journal

      Volume: 35 Issue: 1

    • DOI

      10.1096/fj.202002077r

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ATR inhibition enhances 5-fluorouracil sensitivity independent of non-homologous end-joining and homologous recombination repair pathway2020

    • Author(s)
      Ito SS, Nakagawa Y, Matsubayashi M, Sakaguchi YM, Kobashigawa S, Matsui TK, Nanaura H, Nakanishi M, Kitayoshi F, Kikuchi S, Kajihara A, Tamaki S, Sugie K, Kashino G, Takahashi A, Hasegawa M, Mori E
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/2020.04.20.051318

    • Related Report
      2019 Research-status Report
    • Open Access
  • [Journal Article] Brainstem organoids from human pluripotent stem cells contain neural crest population2020

    • Author(s)
      Eura N et al.
    • Journal Title

      Frontiers in Neuroscience

      Volume: -

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Human URAT1/SLC22A12 gene promoter is regulated by 27-hydroxycholesterol through estrogen response elements2019

    • Author(s)
      Matsubayashi M, Sakaguchi YM, Sahara Y, Nanaura H, Kikuchi S, Ashari A, Bui L, Kobashigawa S, Nakanishi M, Nagata R, Matsui TK, Kashino G, Hasegawa M, Takasawa S, Eriguchi M, Tsuruya K, Nagamori S, Sugie K, Nakagawa T, Takasato M, Umetani M, Mori E
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/827709

    • Related Report
      2019 Research-status Report
    • Open Access / Int'l Joint Research
  • [Journal Article] Stress-induced Cellular Senescence Contributes to Chronic Inflammation and Cancer Progression2019

    • Author(s)
      Kobashigawa S, Sakaguchi YM, Masunaga S, Mori E
    • Journal Title

      Thermal Medicine

      Volume: 35(4) Pages: 41-58

    • NAID

      130007789965

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Mitochondrial ROS by ionizing radiation induce cellular senescence through ATM activation2021

    • Author(s)
      Shinko Kobashigawa, Genro Kashino
    • Organizer
      日本放射線影響学会 第64回大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Delayed reactive oxygen species contribute to radiation-induced cellular senescence2021

    • Author(s)
      Shinko Kobashigawa, Genro Kashino, Aki Niinomi, Eiichiro Mori
    • Organizer
      日本放射線影響学会第63回大会
    • Related Report
      2020 Research-status Report
  • [Presentation] グルコピラノシルアスコルビン酸の照射後処理による正常細胞の防護効果2020

    • Author(s)
      小橋川新子、新家英、菓子野元郎、森英一朗
    • Organizer
      第22回菅原・大西記念癌治療増感シンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] Different response to radiation-induced delayed oxidative stress in normal cells and cancer cells.2020

    • Author(s)
      Kobashigawa S., Niinomi A., Kashino G., Mori E
    • Organizer
      The 8th GIAR International Symposium
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Delayed ROS related to mitochondrial fission causes cellular senescence after radiation exposure.2019

    • Author(s)
      Kobashigawa S., Mori E
    • Organizer
      ASUKA Symposium 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 遅発性活性酸素種に対する正常細胞とがん細胞との応答の違いはあるのか2019

    • Author(s)
      小橋川新子、新家英、菓子野元郎、森英一朗
    • Organizer
      日本放射線影響学会 第62回大会
    • Related Report
      2019 Research-status Report
  • [Remarks] ACHIEVEMENTS

    • URL

      https://www.mirai-nmu.com/pages/934528/page_201704052138

    • Related Report
      2020 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2024-01-30  

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