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造血幹細胞におけるRSと細胞内小器官との関連検討によるBMF発症メカニズムの解明

Research Project

Project/Area Number 21K08425
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionTokyo Women's Medical University

Principal Investigator

望月 牧子  東京女子医科大学, 医学部, 助教 (40751300)

Project Period (FY) 2021-04-01 – 2025-03-31
Project Status Granted (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords骨髄不全症 / ファンコニ貧血 / 造血幹細胞 / エネルギー代謝 / TPOシグナル / 骨髄不全症候群 / RS / BMF / FA / Fancd2 / HSC
Outline of Research at the Start

FA分子の主な作用点であるDNA複製ストレス (RS)応答がその不全によってどのようにHSCを変化させるのか、またそれによってどの様 にBMFを発症させるのか、そのメカニズムを明らかにする 。そのためにFA HSC の細胞内小器官の変化に着目しながら解析を進める。

Outline of Annual Research Achievements

本研究はFA分子の主な作用点であるDNA複製ストレス (RS)応答がその不全によってどのように造血幹細胞(HSC)を変化させるのか、またそれによってどの様 に骨髄不全症(BMF)を発症させるのか、そのメカニズムを明らかにすることを目的として、特にFA HSC の細胞内小器官の変化に着目しながら解析してきた。これまでの結果より胎児FA造血幹細胞でミトコンドリアOXPHOSの上昇がみられたことから、今年度はOXPHOSを調整する目的でTPOシグナルの増減を行ない、幹細胞能について評価した。その結果、TPO発現を半減させるとOXPHOSは低下するものの、造血幹細胞数の回復にはつながらなかった。

Current Status of Research Progress
Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

論文は昨年度報告した為、その知見に基づいた新たな検討を継続して行なっている。
骨髄不全症の解明の為に継続して努力してゆきたい。

Strategy for Future Research Activity

今後は新たに作成したFAコンディショナル欠損マウスを用いて生体内の細かなメカニズムについて明らかにしていきたい。

Report

(3 results)
  • 2023 Research-status Report
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (15 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (1 results) Journal Article (6 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 6 results,  Open Access: 5 results) Presentation (8 results) (of which Int'l Joint Research: 2 results)

  • [Int'l Joint Research] St. Jude Children's Hospital/University of Philadelphia(米国)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Long-term combination therapy with Metformin and Oxymetholone in a Fanconi Anemia mouse model2024

    • Author(s)
      orrell C, Peters AM, Zhang Q, Balaji N, Baradar K, Mochizuki-Kashio M, Major A, Finegold M, Liu C, Lu K, Grompe M
    • Journal Title

      Pediatric Blood & Cancer

      Volume: -

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Abcb10 regulates murine hematopoietic stem cell potential and erythroid differentiation2024

    • Author(s)
      Yahagi Ayano、Mochizuki-Kashio Makiko、Sorimachi Yuriko、Takubo Keiyo、Nakamura-Ishizu Ayako
    • Journal Title

      Experimental Hematology

      Volume: - Pages: 104191-104191

    • DOI

      10.1016/j.exphem.2024.104191

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Deregulated protein homeostasis constrains fetal hematopoietic stem cell pool expansion in Fanconi anemia2024

    • Author(s)
      Kovuru Narasaiah、Mochizuki-Kashio Makiko、Menna Theresa、Jeffrey Greer、Hong Yuning、me Yoon Young、Zhang Zhe、Kurre Peter
    • Journal Title

      Nature Communications

      Volume: 15 Issue: 1

    • DOI

      10.1038/s41467-024-46159-1

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Editorial: Advances in predisposition to bone marrow failure and hematopoietic neoplasms2024

    • Author(s)
      Sahoo Sushree S.、Abdelhamed Sherif、Mochizuki-Kashio Makiko、Wahlster Lara
    • Journal Title

      Frontiers in Oncology

      Volume: 14

    • DOI

      10.3389/fonc.2024.1377974

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells.2023

    • Author(s)
      Makiko Mochizuki-Kashio, Noriko Otsuki, Kota Fujiki, Sherif Abdelhamd, Peter Kurre, Markus Grompe, Atsushi Iwama, Kayoko Saito, Ayako Nakamura-Ishizu
    • Journal Title

      Frontiers in Oncology

      Volume: 13 Pages: 1108430-1108430

    • DOI

      10.3389/fonc.2023.1108430

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mitochondria Turnover and Lysosomal Function in Hematopoietic Stem Cell Metabolism2021

    • Author(s)
      Mochizuki-Kashio Makiko、Shiozaki Hiroko、Suda Toshio、Nakamura-Ishizu Ayako
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 9 Pages: 4627-4627

    • DOI

      10.3390/ijms22094627

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] TPO agonist rescued developmental hematopoietic stem cell in hereditary bone marrow failure syndrome2024

    • Author(s)
      Makiko Mochizuki-Kashio, Ayano Yahagi, Tomomasa Yokomizo, Ayako Nakamura-Ishizu
    • Organizer
      3rd Regional Symposium on Myelodysplastic Syndromes (MDSR 2024)
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research
  • [Presentation] Life stage-dependent regulation of distinct hematopoietic stem and progenitor populations via Thrombopoietin signaling2024

    • Author(s)
      Makiko Mochizuki-Kashio, Ayano Yahagi, Tomomasa Yokomizo, Ayako Nakamura-Ishizu
    • Organizer
      日本血液学会
    • Related Report
      2023 Research-status Report
  • [Presentation] Fanconi Anemia-related replication stress increases metabolic activity in fetal liver hematopoietic stem cells2022

    • Author(s)
      Makiko Mochizuki-Kashio, Ayako Nakamura-Ishizu
    • Organizer
      9thSCRS
    • Related Report
      2022 Research-status Report
  • [Presentation] Ptprd regulates hematopoietic stem cells through their miniexon domains2022

    • Author(s)
      Makiko Mochizuki-Kashio, Kohtaro Takizawa, Fumio Nakamura, Ayako Nakamura-Ishizu
    • Organizer
      日本血液学会
    • Related Report
      2022 Research-status Report
  • [Presentation] Fanconi Anemia-related replication stress increases cytosolic activity2022

    • Author(s)
      Makiko Mochizuki-Kashio
    • Organizer
      64th ASH
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Fanconi Anemia protein FANCD2 confers with Replication Stress through the Hematopoietic Stem Cell expansion in Fetal Liver2021

    • Author(s)
      Makiko Mochizuki-Kashio, Young me Yoon, Theresa Menna, Ayako Nakamura-Ishizu, Markus Grompe and Peter Kurre
    • Organizer
      第18回 幹細胞シンポジウム
    • Related Report
      2021 Research-status Report
  • [Presentation] Replication stress accelerates myeloid-bias through the activation of mitochondrial OXPHOS in hematopoietic stem cells2021

    • Author(s)
      Makiko Mochizuki-Kashio, Ayako Nakamura-Ishizu
    • Organizer
      50th ISEH
    • Related Report
      2021 Research-status Report
  • [Presentation] Replication stress accelerates myeloid-bias through the activation of mitochondrial OXPHOS in hematopoietic stem cells2021

    • Author(s)
      Makiko Mochizuki-Kashio, Ayako Nakamura-Ishizu
    • Organizer
      第83回 日本血液学会
    • Related Report
      2021 Research-status Report

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Published: 2021-04-28   Modified: 2024-12-25  

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