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Therapeutic development of immune deficiency with mitochondrial dysfunction using CoQ10

Research Project

Project/Area Number 17K12900
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Eating habits
Research InstitutionPrefectural University of Kumamoto (2018-2019)
The University of Tokushima (2017)

Principal Investigator

Ayako Tanimura  熊本県立大学, 環境共生学部, 助教 (10610199)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsミトコンドリア / エネルギー代謝 / 細網異型性症 / 免疫不全 / 好中球分化 / フルクトース / CoQ10 / 小胞体ストレス / UPR / ATP / ROS / 栄養学 / 好中球 / 細胞分化
Outline of Final Research Achievements

I established a model cell line of reticular dysgenesis which presents similar phenotypes to promyelocytic cells of patients by mutating causative gene AK2 using genome-editing system. One of symptoms in reticular dysgenesis is differentiation arrest of neutrophil differentiation that is thought to be caused by decreased ATP production and/or increased ROS due to impairment of mitochondrial energy production. I tried to improve the impairment of neutrophil differentiation with fructose or MitoQ, a mitochondria-targeted CoQ10 to increase ATP production or decrease ROS respectively. As a results, neutrophil differentiation rate was improved to similar level of that of WT cells by fructose in a model cell line. In addition, I revealed that lower ATP level suppress unfolded protein response (UPR) and then increasing ER stress inhibited neutrophil differentiation. According to this, it was thought that energy metabolism and ER stress/UPR play a critical role on neutrophil differentiation.

Academic Significance and Societal Importance of the Research Achievements

ミトコンドリア機能異常による希少難病であり、免疫不全により出生直後から重篤な感染症を引き起こしうる細網異形成症において、発症機序の一端を明らかにし、それを基に乳児での新規治療法につながりうる候補栄養素を見出した。この成果は、栄養素による免疫機能のコントロールやミトコンドリア異常疾患に対する栄養療法の可能性についても強く期待できるものである。
また、最も数が多い免疫細胞である好中球において、その分化がエネルギー代謝と小胞体ストレスによって調節されていることを明らかにした。このことは好中球の賦活方法の開発や他の免疫細胞の分化機構解明などの一助になりうると考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (10 results)

All 2020 2019 2018 2017 Other

All Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (7 results) (of which Int'l Joint Research: 2 results) Remarks (1 results)

  • [Journal Article] Mitochondrial Activity and Unfolded Protein Response are Required for Neutrophil Differentiation.2018

    • Author(s)
      Tanimura A, Miyoshi K, Horiguchi T, Hagita H, Fujisawa K, Noma T
    • Journal Title

      Cell Physiol Biochem

      Volume: 47 Issue: 5 Pages: 1936-1950

    • DOI

      10.1159/000491464

    • NAID

      120006550810

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Human AK2 links intracellular bioenergetic redistribution to the fate of hematopoietic progenitors2018

    • Author(s)
      Oshima Koichi、Watanabe Akira、Nakahata Tatsutoshi、Saito Megumu K. et al.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 497 Issue: 2 Pages: 719-725

    • DOI

      10.1016/j.bbrc.2018.02.139

    • NAID

      120006466601

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] アデニル酸キナーゼ2欠損血球系細胞の分化に対するフルクトースの効果2020

    • Author(s)
      溝内 万里奈、谷村 綾子、南 久則
    • Organizer
      第23回日本病態栄養学会年次学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] フルクトースはミトコンドリアのエネルギー産生異常による好中球分化障害を改善するか Can Fructose rescue the impairment of neutrophil differentiation due to failure of mitochondrial energy production?2020

    • Author(s)
      谷村 綾子、溝内 万里奈、三好 圭子、堀口 大吾、野間 隆文、南 久則
    • Organizer
      第74回日本栄養・食糧学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 免疫細胞の分化におけるエネルギー産生の必要性 Importance of energy production for immune cell differentiations2019

    • Author(s)
      谷村 綾子、三好 圭子、堀口 大吾、萩田 浩子、野間 隆文、南 久則
    • Organizer
      第73回日本栄養・食糧学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] A role of ER stress and UPR on hematopoietic differentiation2018

    • Author(s)
      Ayako Tanimura, Keiko Miyoshi, Taigo Horiguchi, Hagita Hiroko, Koichi Fujisawa and Takafumi Noma
    • Organizer
      51st Miami Winter Symposium, Stem Cells Todays Research Tomorrows Therapies
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Impact of mitochondrial ATP production on neutrophil differentiation2017

    • Author(s)
      Ayako Tanimura, Keiko Miyoshi, Taigo Horiguchi, Hagita Hiroko, Koichi Fujisawa and Takafumi Noma
    • Organizer
      Gordon Research Conference(From Molecular Structures and Mechanisms to Cellular Bioenergetics in Health and Disease)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] ミトコンドリアがUPR活性をコントロールして免疫細胞分化の方向を決定づける2017

    • Author(s)
      谷村 綾子, 三好 圭子, 堀口 大吾, 萩田 浩子, 藤澤 浩一, 野間 隆文
    • Organizer
      第17回日本ミトコンドリア学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] CRISPR/Cas9を用いたAK2の段階的欠損による細胞代謝への影響2017

    • Author(s)
      谷村 綾子, 三好 圭子, 堀口 大吾, 藤澤 浩一, 野間 隆文
    • Organizer
      日本ゲノム編集学会 第2回大会
    • Related Report
      2017 Research-status Report
  • [Remarks] ヒトAK2は細胞内エネルギー分子の分配を介して血液前駆細胞の分化運命を制御する

    • URL

      http://www.cira.kyoto-u.ac.jp/j/research/finding/180328-110000.html

    • Related Report
      2017 Research-status Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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