過栄養ストレスによる幹細胞運命決定機構とエイジング

• Project Area: Establishing a new paradigm of the pathogenesis of diseases through the understanding of stem cell aging
• Project/Area Number: 17H05638
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kanazawa 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): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 造血幹細胞 / 腸内細菌叢 / エイジング / 幹細胞分化

Outline of Annual Research Achievements

本研究では，高脂肪食という栄養的ストレス下において，造血幹細胞の恒常性を保つための機構を理解することを目的とした。本年度は、昨年に引き続き、Spred1の高脂肪食における役割を解析した。高脂肪食による過栄養状態では，Spred1欠損造血幹細胞の機能障害が生じることが観察されたため、そのメカニズムの解明を目指し、腸内細菌叢との関連を検討した。まず、野生型マウスとSpred1欠損マウスの両者を普通食および高脂肪食群、計4群に分け、それぞれのマウスから糞便を採取し、16S rRNAを次世代シークエンサーにて解析し、細菌叢の変化を観察した。予想通り、高脂肪食群では、グラム陰性菌の増加が観察された。Spred1欠損の有無によって、腸内細菌叢の違いは顕著には認められなかった。ただし、詳細に観察することで、Spred1特有の細菌叢が存在する可能性も示されたため、今後の検討が必要である。腸内細菌叢を除去する目的で、抗生剤カクテルを投与したところ、血液異常は部分的に回復した。また、造血幹細胞の機能低下も有意に回復した。以上の結果より、Spred1欠損マウスでは、腸内細菌叢の異常が造血幹細胞に作用し、造血異常を引き起こしていると考えられた。また、Spred1は、異常な食餌（高脂肪食）による環境変化に対して、造血幹細胞を保護する役割を有することが明らかとなった。本シグナルの詳細な解析と人為的に変化させる技術開発を進めることによって、幹細胞老化の本態を理解し、アンチエイジングなどの革新的医療技術の開発に寄与できると考えられた。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] スタンフォード大学(米国)
• [Journal Article] Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function (2019)
  • Author(s): Imanishi Takayuki、Unno Midori、Kobayashi Wakana、Yoneda Natsumi、Matsuda Satoshi、Ikeda Kazutaka、Hoshii Takayuki、Hirao Atsushi、Miyake Kensuke、Barber Glen N、Arita Makoto、Ishii Ken J、Akira Shizuo、Saito Takashi
  • Journal Title: Life Science Alliance Volume: 2 Issue: 1 Pages: e201800282-e201800282
  • DOI: 10.26508/lsa.201800282
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress (2018)
  • Author(s): Tadokoro Yuko、Hoshii Takayuki、Yamazaki Satoshi、Eto Koji、Ema Hideo、Kobayashi Masahiko、Ueno Masaya、Ohta Kumiko、Arai Yuriko、Hara Eiji、Harada Kenichi、Oshima Masanobu、Oshima Hiroko、Arai Fumio、Yoshimura Akihiko、Nakauchi Hiromitsu、Hirao Atsushi
  • Journal Title: Cell Stem Cell Volume: 22 Issue: 5 Pages: 713-725
  • DOI: 10.1016/j.stem.2018.04.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas. (2018)
  • Author(s): Vu HT, Kobayashi M, Hegazy AM, Tadokoro Y, Ueno M, Kasahara A, Takase Y, Nomura N, Peng H, Ito C, Ino Y, Todo T, Nakada M, Hirao A
  • Journal Title: Cancer Science Volume: 109 Issue: 8 Pages: 2497-2508
  • DOI: 10.1111/cas.13695
  • Peer Reviewed / Open Access
• [Journal Article] JLP-JNK signaling protects cancer cells from reactive oxygen species-induced cell death (2018)
  • Author(s): Li Rong、Gunarta I. Ketut、Suzuki Ryusuke、Boldbaatar Jambaldorj、Nakazato Ryota、Yuliana Dewi、Davaakhuu Gantulga、Oyunsuren Tsendsuren、Takamatsu Nobuhiko、Kobayashi Masahiko、Hirao Atsushi、Yoshioka Katsuji
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 501 Issue: 3 Pages: 724-730
  • DOI: 10.1016/j.bbrc.2018.05.055
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Distinct roles of Rheb and Raptor in activating mTOR complex 1 for the self-renewal of hematopoietic stem cells (2018)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spred1 safeguards hematopoietic homeostasis against diet-induced systemic stress. (2018)
  • 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
  • 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 expression (2017)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug (2017)
  • 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: 111728-111741
  • DOI: 10.18632/oncotarget.22904
  • Peer Reviewed / Open Access
• [Presentation] Metabolic Regulation of Stemness in Malignant Hematopoiesis (2019)
  • Author(s): Hirao A
  • Organizer: Eleventh AACR-JCA Joint Conference on Breakthroughs in Cancer Research: Biology to Precision Medicine
  • Int'l Joint Research / Invited
• [Presentation] The nutrient signals in self-renewal of hematopoietic stem cells and tumorigenesis (2019)
  • Author(s): Hirao A
  • Organizer: 2019 US-Japan Symposium on Normal/Malignant Hematopoiesis and Novel Therapies for Hematologic Malignancies
  • Int'l Joint Research / Invited
• [Presentation] Metabolic Regulation of Stemness in Malignant Hematopoiesis (2018)
  • Author(s): Hirao A
  • Organizer: International symposium on drug discovery (Joint symposium of Univ. of Tokyo and Novartis Institute)
  • Int'l Joint Research / Invited
• [Presentation] Metabolic Control of Cancer Stemness. (2018)
  • Author(s): Hirao A
  • Organizer: The 2nd NanoLSI Symposium in London Towards Establishment of New Research Field: Nanoprobe Life Science-
  • Int'l Joint Research / Invited
• [Presentation] Regulation of stem cell properties by metabolic signals in hematopoietic neoplasm (2018)
  • Author(s): Hirao A
  • Organizer: JSPS - National University of Singapore (NUS) 2nd Symposium.
  • 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.
  • 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.
  • 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
  • Invited