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幹細胞発生・分化におけるオートファジーチェックポイント機構

Publicly Offered Research

Project AreaMultidisciplinary research on autophagy: from molecular mechanisms to disease states
Project/Area Number 16H01199
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKanazawa University

Principal Investigator

平尾 敦  金沢大学, がん進展制御研究所, 教授 (90343350)

Project Period (FY) 2016-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2017: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2016: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Keywords幹細胞 / オートファジー / 幹細胞分化 / 造血幹細胞
Outline of Annual Research Achievements

本研究では、オートファジーが、どのように成体型造血幹細胞の成立に寄与するのか、また、関連した研究として、腫瘍幹細胞におけるオートファジーの意義を明らかにすることを目標とした。本年度は、オートファジーと深く関与するmTOR複合体1 (mTORC1)の生体内での造血幹細胞の自己複製能の役割を明らかにするため、Rheb変異マウス(Rheb f/f CreER)の骨髄細胞を放射線照射マウスに移植し、骨髄再構築が完了した後に、タモキシフェンを投与し、野生型造血細胞との競合状態を評価した。その結果、Rheb欠損による明確な造血幹細胞異常は認められないことが判明した。さらに、マウスに低線量のX線を照射しても、その結果には影響をしていなかった。したがって、定常状態および傷害ストレス下においてもRheb依存的な幹細胞の異常は認められなかった。一方、Raptor欠損に関しては顕著な造血幹細胞の現象が認められることから、mTORC1自体は造血幹細胞の自己複製に必須であるが、PI3K-AKT以外の上流の重要性が示唆された。また、オートファジーの活性化による造血幹細胞保護作用の可能性が示された。以上のように、本研究成果は、オートファジーの役割を明確にするための意義ある情報となった。また、脳腫瘍幹細胞において、ATG5遺伝子を破壊し、未分化性に関する指標を解析した結果、オートファジー不全状態は、通常状態では何ら影響を及ぼさないものの、ミトコンドリア傷害性の抗がん剤に対する感受性の亢進に寄与することが判明した。本成果により、将来、臨床的に有用な治療法の開発に寄与する可能性が示唆された。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (15 results)

All 2018 2017 2016

All Journal Article (7 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 7 results,  Open Access: 4 results,  Acknowledgement Compliant: 1 results) Presentation (7 results) (of which Int'l Joint Research: 5 results,  Invited: 7 results) Book (1 results)

  • [Journal Article] Distinct roles of Rheb and Raptor in activating mTOR complex 1 for the self-renewal of hematopoietic stem cells2018

    • Author(s)
      Hui Peng, Atsuo Kasada, Masaya Ueno, Takayuki Hoshii, Yuko Tadokoro, Naho Nomura, Chiaki Ito, Yusuke Takase, Ha Thi Vu, Masahiko Kobayashi, Bo Xiao, Paul F. Worley, Atsushi Hirao
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 495 Issue: 1 Pages: 1129-1135

    • DOI

      10.1016/j.bbrc.2017.11.140

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Spred1 safeguards hematopoietic homeostasis against diet-induced systemic stress. Cell Stem Cell2018

    • Author(s)
      Tadokoro Y, Hoshii T, Yamazaki S, Eto K, Ema H, Kobayashi M Ueno M, Ohta K, Arai Y, Hara E, Harada K, Oshima M, Oshima H, Arai F, Yoshimura A, Nakauchi N, Hirao A.
    • Journal Title

      Cell Stem Cell

      Volume: 印刷中

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Functional dissection of hematopoietic stem cell populations with a stemness-monitoring system based on NS-GFP transgene expression2017

    • Author(s)
      Ali Mohamed A. E.、Fuse Kyoko、Tadokoro Yuko、Hoshii Takayuki、Ueno Masaya、Kobayashi Masahiko、Nomura Naho、Vu Ha Thi、Peng Hui、Hegazy Ahmed M.、Masuko Masayoshi、Sone Hirohito、Arai Fumio、Tajima Atsushi、Hirao Atsushi
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 11442-11442

    • DOI

      10.1038/s41598-017-11909-3

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug2017

    • Author(s)
      Dong Y, Furuta T, Sabit H, Kitabayashi T, Jiapaer S, Kobayashi M, Ino Y, Todo T, Teng L, Hirao A, Zhao SG, Nakada M
    • Journal Title

      Oncotarget

      Volume: 8 Issue: 67 Pages: 111728

    • DOI

      10.18632/oncotarget.22904

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Therapeutic strategy for targeting aggressive malignant gliomas by disrupting their energy balance2016

    • Author(s)
      Hegazy AM, Yamada D, Kobayashi M, Kohno S, Ueno M, Ali MA, Ohta K, Tadokoro Y, Ino Y, Todo T, Soga T, Takahashi C, Hirao A.
    • Journal Title

      J Biol Chem.

      Volume: 291 Issue: 41 Pages: 21496

    • DOI

      10.1074/jbc.m116.734756

    • URL

      https://pure.teikyo.jp/en/publications/4fe8f15b-bacb-416b-913c-78075a763db0

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MIP-1α/CCL3-expressing basophil-lineage cells drive the leukemic hematopoiesis of chronic myeloid leukemia in mice.2016

    • Author(s)
      Baba T, Tanabe Y, Yoshikawa S, Yamanishi Y, Morishita S, Komatsu N, Karasuyama H, Hirao A, Mukaida N
    • Journal Title

      Blood

      Volume: 印刷中 Issue: 21 Pages: 2607-17

    • DOI

      10.1182/blood-2015-10-673087

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Cooperative networks for stem cell homeostasis in normal and malignant hematopoiesis: from metabolism to epigenetics.2016

    • Author(s)
      Hirao A.
    • Journal Title

      Int J Hematol

      Volume: 103 Issue: 6 Pages: 605-6

    • DOI

      10.1007/s12185-016-2012-4

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Presentation] Regulation of stem cell properties by metabolic signals in hematopoietic neoplasm2018

    • Author(s)
      Hirao A
    • Organizer
      JSPS - National University of Singapore (NUS) 2nd Symposium.
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Hematopoietic stem cell homeostasis under diet-induced systemic stress.2017

    • Author(s)
      Hirao A
    • Organizer
      The joint symposium on tumor microenvironemnt and precision medicine.
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Regulation of stem cell properties by nutrient signals in hematopoietic neoplasms.2017

    • Author(s)
      Hirao A
    • Organizer
      2017 Cancer Biology Symposium.
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 造血幹細胞の運命決定機構ー自己複製の異常と疾患ー2017

    • Author(s)
      平尾敦
    • Organizer
      第7回細胞再生医療学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 栄養シグナルと幹細胞制御2016

    • Author(s)
      平尾敦
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-12-01
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Molecular mechanism linking between hematopoietic stem cell aging and leukemogenesis.2016

    • Author(s)
      Hirao A
    • Organizer
      46th International Symposium of the Princess Takamatsu Cancer Research Fund
    • Place of Presentation
      Tokyo
    • Year and Date
      2016-11-07
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Molecular mechanism linking hematopoietic stem cell aging and leukemogenesis.2016

    • Author(s)
      Hirao A
    • Organizer
      Fifth JCA-AACR Special Joint Conference on the Latest Advances in Hematological Cancer Research
    • Place of Presentation
      Urayasu, Chiba
    • Year and Date
      2016-07-13
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Book] Regulation of Hematopoiesis and Hematological Disease by TGF-b Family Signaling Molecules2017

    • Author(s)
      Naka K., Hirao A
    • Total Pages
      5
    • Publisher
      Cold Spring Harbor Laboratory Press
    • Related Report
      2016 Annual Research Report

URL: 

Published: 2016-04-26   Modified: 2018-12-17  

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