幹細胞エイジングを制する栄養環境シグナルメディエーター

• Project Area: Establishing a new paradigm of the pathogenesis of diseases through the understanding of stem cell aging
• Project/Area Number: 15H01509
• 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): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: 造血幹細胞 / エイジング

Outline of Annual Research Achievements

本研究では、造血幹細胞の自己複製制御機構の理解により、幹細胞老化の分子基盤を明らかにすることを目標に，Spredファミリーの機能解析を進めた。Spred1は，SCF/c-Kitにより活性化され，Ras-Raf-ERK経路を負に制御ことが知られている。そこで、造血幹細胞において，Spred1とc-Kitシグナルとの関係を解析した。予備的検討により、本分子が造血幹細胞の自己複製を負に制御すること，炎症など様々なストレスに反応して上昇し，幹細胞機能を抑制することを見いだした。また，造血幹細胞の細胞分裂の際，足場となるニッチ細胞や接着を介した自己複製調節が重要であることを見いだした。加齢による造血幹細胞の異常との関連を解析するため、Spred1欠損老齢マウスの造血を解析した。その結果、100週齢を越えた野生型マウスにおいては、Spred1の発現レベルが上昇していること、移植実験により、加齢による幹細胞機能の抑制が回避できることが観察された。一方，Spred2の欠損は、ほとんど造血異常を示さず、移植実験による造血幹細胞機能の亢進は認められなかった。以上の知見より、幹細胞老化において本分子を介した自己複製能の制御が深く関与していること、さらに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

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Therapeutic strategy for targeting aggressive malignant gliomas by disrupting their energy balance (2016)
  • 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
  • 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
  • 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
  • Peer Reviewed
• [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
  • Peer Reviewed
• [Journal Article] The PI3K-Akt pathway controls IL-10-producing regulatory B cells. (2016)
  • Author(s): MatsushitaT, Huu DL, Hamaguchi Y, Hasegawa M, Naka K, Hirao A, Muramatsu M, Takehara K, Fujimoto M.
  • Journal Title: J Allergy Clin Immunol Volume: 印刷中 Issue: 4 Pages: 21496-21509
  • DOI: 10.1016/j.jaci.2015.12.1319
  • Peer Reviewed
• [Journal Article] Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells. (2016)
  • Author(s): Naka K, Ishihara K, Jomen Y, Jin CH, Kim DH, Gu YK, Jeong ES, Li S, Krause DS, Kim DW, Bae E, Takihara Y, Hirao A, Oshima H, Oshima M, Ooshima A, Sheen YY, Kim SJ, Kim DK.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 2 Pages: 140-148
  • DOI: 10.1111/cas.12849
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142 (2015)
  • Author(s): Teppei Kawahara, Noritaka Kagaya, Yuichi Masuda, Takayuki Doi, Miho Izumikawa, Kumiko Ohta, Atsushi Hirao, Kazuo Shin-ya
  • Journal Title: Organic letters Volume: 17 Issue: 21 Pages: 5476-5479
  • DOI: 10.1021/acs.orglett.5b02842
  • Peer Reviewed / Open Access
• [Journal Article] S6 Kinase- and beta-TrCP2-Dependent Degradation of p19Arf Is Required for Cell Proliferation (2015)
  • Author(s): Nakagawa T, Araki T, Nakagawa M, Hirao A, Unno M, Nakayama K
  • Journal Title: Molecular and cellular biology Volume: 20 Issue: 20 Pages: 3517-3527
  • DOI: 10.1128/mcb.00343-15
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
  • 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
  • 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
  • Int'l Joint Research / Invited
• [Presentation] 造血・白血病幹細胞研究の現状と未来. (2015)
  • Author(s): 平尾敦
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: ホテル金沢（金沢市、石川県）
  • Year and Date: 2015-10-16
  • Invited
• [Presentation] Molecular mechanism linking between hematopoietic stem cell aging and leukemogenesis. (2015)
  • Author(s): Hirao A
  • Organizer: International Society for Experimental Hematology（ISEH） 44th Annual Scientific Meeting
  • Place of Presentation: 京都国際会議場（京都市、京都府）
  • Year and Date: 2015-09-17
  • Int'l Joint Research / Invited
• [Presentation] Role of nutrient sensing signaling pathways in the maintenance of leukemia stem cells. (2015)
  • Author(s): Hirao A
  • Organizer: SNUCRI CANCER SYMPOSIUM
  • Place of Presentation: Kumho Hwasun Resort(Hwasun, Korea)
  • Year and Date: 2015-04-03
  • Int'l Joint Research / Invited
• [Book] Regulation of Hematopoiesis and Hematological Disease by TGF-b Family Signaling Molecules (2017)
  • Author(s): Naka K., Hirao A
  • Total Pages: 5
  • Publisher: Cold Spring Harbor Laboratory Press
• [Book] Molecular Pathogenesis and Treatment of Chronic Myelogenous leukemia (2015)
  • Author(s): Hirao A, Tadokoro Y, Ueno M
  • Publisher: Springer