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造血幹細胞の機能維持を司るリボソーム生合成経路の検証

Publicly Offered Research

Project AreaEstablishing a new paradigm of the pathogenesis of diseases through the understanding of stem cell aging
Project/Area Number 15H01513
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 InstitutionKumamoto University

Principal Investigator

松井 啓隆  熊本大学, 大学院生命科学研究部(医), 教授 (60379849)

Project Period (FY) 2015-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2015: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Keywordsリボソーム生合成 / 造血幹細胞 / 老化
Outline of Annual Research Achievements

近年、造血幹細胞領域を中心に、加齢によるリボソームの変化が注目されつつある。リボソームの機能は過剰にすぎても抑制されてもHSCの可塑性維持に不都合が生じることがわかってきた。リボソームを構成する因子は約80種類のリボソームタンパク質と4種類のリボソームRNA(rRNA)であるが、この生合成には多くの因子が必要で、とりわけpre-rRNAのプロセシングは、数百に及ぶトランス因子の作用で段階的に秩序だって行われる。また、リボソームDNA(rDNA)領域は、合計数百のrDNA遺伝子により構成され、数多くの複製開始点を有することが知られる。最近、この領域のDNA複製障害の蓄積が老化造血細胞の特徴のひとつであることが提唱されており、リボソーム生合成のコントロールを起点とした細胞制御システムが加齢現象に深く関わることが注目されつつある。
こうしたことを背景とし、本研究では造血細胞の加齢変化をリボソーム変化として捉えることに注力してきた。まず、老化HSCでは、リボソーム合成関連因子が広汎に発現低下することを見出した。また、これに伴ってDNA複製システムの機能抑制が起こることも確認された。この実験では、造血細胞においてpre-rRNAプロセシングに関与するDDX41のドミナント・ネガティブ変異体を発現させた。これによって、pre-rRNAのプロセシングが障害され、成熟rRNAの合成が抑制されたが、この際、DNA複製に関わる多くの因子の遺伝子発現低下が認められ、これは老化HSCの遺伝子発現変化と酷似していた。こうした結果は、我々の当初の予想どおり、リボソーム生合成経路の機能抑制が加齢変化に直接関与することを示唆しており、また、リボソーム生合成障害がDNA複製ストレスを惹起することを想起させた。両者を結びつけるシグナル伝達経路を特定することが今後の研究課題といえる。

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。

Report

(2 results)
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (27 results)

All 2017 2016 2015

All Journal Article (13 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 13 results,  Open Access: 6 results,  Acknowledgement Compliant: 4 results) Presentation (13 results) (of which Int'l Joint Research: 4 results,  Invited: 2 results) Book (1 results)

  • [Journal Article] A case of pulmonary thromboembolism due to coagulation factor V Leiden in Japan ~Usefulness of next generation sequencing~.2017

    • Author(s)
      Sueta D, Ito M, Uchiba M, Sakamoto K, Yamamoto E, Izumiya Y, Kojima S, Kaikita K, Shinriki S, Hokimoto S, Matsui H, Tsujita K.
    • Journal Title

      Thromb. J

      Volume: in press Issue: 1

    • DOI

      10.1186/s12959-017-0132-6

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia.2017

    • Author(s)
      Okuda H, Stanojevic B, Kanai A, Kawamura T, Takahashi S, Matsui H, Takaori-Kondo A, Yokoyama A.
    • Journal Title

      J. Clin. Invest.

      Volume: in press Issue: 5 Pages: 1918-1931

    • DOI

      10.1172/jci91406

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers.2017

    • Author(s)
      Sugino N, Kawahara M, Tatsumi G, Kanai A, Matsui H, Yamamoto R, Nagai Y, Fujii S, Shimazu Y, Hishizawa M, Inaba T, Andoh A, Suzuki T, Takaori-Kondo A.
    • Journal Title

      Leukemia

      Volume: in press Issue: 11 Pages: 2303-2314

    • DOI

      10.1038/leu.2017.59

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome.2016

    • Author(s)
      Hasegawa N, Oshima M, Sashida G, Matsui H, Koide S, Saraya A, Wang C, Muto T, Takane K, Kaneda A, Shimoda K, Nakaseko C, Yokote K, Iwama A.
    • Journal Title

      Leukemia

      Volume: in press Issue: 4 Pages: 861-871

    • DOI

      10.1038/leu.2016.268

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Propagation of tri-methylated H3K27 regulated by EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression.2016

    • Author(s)
      Ueda T, Nakata Y, Nagamachi A, Yamasaki N, Kanai A, Matsui H, Honda ZI, Oda H, Wolff L, Inaba T, Honda H.
    • Journal Title

      PNAS

      Volume: 113(37) Issue: 37 Pages: 10370-10375

    • DOI

      10.1073/pnas.1600070113

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Hereditary amyloidosis with cardiomyopathy caused by the novel variant transthyretin A36D.2016

    • Author(s)
      Yamashita T, Ueda M, Saga N, Nanto K, Tasaki M, Masuda T, Misumi Y, Oda S, Fujimoto A, Amano T, Takamatsu K, Yamashita S, Obayashi K, Matsui H, Ando Y.
    • Journal Title

      Amyloid

      Volume: in press Issue: 3 Pages: 207-208

    • DOI

      10.1080/13506129.2016.1202228

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A new variant of acute promyelocytic leukemia with IRF2BP2-RARA fusion.2016

    • Author(s)
      Shimomura Y, Mitsui H, Yamashita Y, Kamae T, Kanai A, Matsui H, Ishibashi T, Tanimura A, Shibayama H, Oritani K, Kuyama J, Kanakura Y.
    • Journal Title

      Cancer Sci.

      Volume: 107(8) Issue: 8 Pages: 1165-1168

    • DOI

      10.1111/cas.12970

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biological implication of somatic DDX41 p.R525H mutation in acute myeloid leukemia.2016

    • Author(s)
      Kadono M, Kanai A, Nagamachi A, Shinriki S, Kawata J, Iwato K, Kyo T, Oshima K, Yokoyama A, Kawamura T, Nagase R, Inoue D, Kitamura T, Inaba T, Ichinohe T, Matsui H.
    • Journal Title

      Exp. Hematol.

      Volume: 44(8) Issue: 8 Pages: 745-754

    • DOI

      10.1016/j.exphem.2016.04.017

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of non-hematopoietic genes.2016

    • Author(s)
      Koide S, Oshima M, Takubo K, Yamazaki S, Nitta E, Saraya A, Aoyama K, Kato Y, Miyagi S, Nakajima-Takagi Y, Chiba T, Matsui H, Arai F, Suzuki Y, Kimura H, Nakauchi H, Suda T, Shinkai Y,Iwama A.
    • Journal Title

      Blood

      Volume: 128(5) Issue: 5 Pages: 638-649

    • DOI

      10.1182/blood-2016-01-694810

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2.2015

    • Author(s)
      Ueda T, Nagamachi A, Takubo K, Yamasaki N, Matsui H, Kanai A, Nakata Y, Ikeda K, Konuma T, Oda H, Wolff L, Honda Z, Wu X, Helin K, Iwama A, Suda T, Inaba T, Honda H
    • Journal Title

      Blood

      Volume: 125 Pages: 3437-3446

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] AF4 uses the SL1 components of RNAP1 machinery to initiate MLL fusion- and AEP-dependent transcription.2015

    • Author(s)
      Okuda H, Kanai A, Ito S, Matsui H, Yokoyama A.
    • Journal Title

      Nat Commun 23

      Volume: 6 Pages: 8869-8869

    • NAID

      120005672585

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Emergence of resistant variants detected by ultra-deep sequencing after asunaprevir and daclatasvir combination therapy in patients infected with hepatitis C virus genotype 12015

    • Author(s)
      Kosaka K, Imamura M, Hayes CN, Abe H, Hiraga N, Yoshimi S, Murakami E, Kawaoka T, Tsuge M, Aikata H, Miki D, Ochi H, Matsui H, Kanai A, Inaba T, Chayama K
    • Journal Title

      J Viral Hepat

      Volume: 22 Pages: 158-165

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.2015

    • Author(s)
      Inoue D, Kitaura J, Matsui H, Hou HA, Chou WC, Nagamachi A, Kawabata KC, Togami K, Nagase R, Horikawa S, Saika M, Micol JB, Hayashi Y, Harada Y, Harada H, Inaba T, Tien HF, Abdel-Wahab O, Kitamura T.
    • Journal Title

      Leukemia

      Volume: 29 Pages: 847-857

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] リボソーム生合成経路の障害による造血器腫瘍の発症メカニズム.2016

    • Author(s)
      神力悟, 松井啓隆.
    • Organizer
      第20回造血器腫瘍研究会
    • Place of Presentation
      木更津
    • Year and Date
      2016-02-12
    • Related Report
      2015 Annual Research Report
  • [Presentation] 休眠骨髄播種癌細胞が自律的に有する分子学的特性.2016

    • Author(s)
      神力悟, 松井啓隆
    • Organizer
      新学術領域「幹細胞老化と疾患」若手の会
    • Place of Presentation
      熱海
    • Year and Date
      2016-01-29
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒト遺伝子検査の現状と展望2016

    • Author(s)
      松井啓隆
    • Organizer
      日本臨床化学会 第56回年次学術集会 (教育講演)
    • Place of Presentation
      熊本
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Somatic DDX41 p.R525H mutation causes growth defect in hematopoietic cells.2016

    • Author(s)
      Matsui H, Nagamachi A, Kanai A, Inaba T
    • Organizer
      第21回欧州血液学会年次総会
    • Place of Presentation
      デンマーク コペンハーゲン
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Impaired hematopoietic cell growth caused by the expression of p.R525H DDX41 mutation.2016

    • Author(s)
      Matsui H, Kanodo M, Kanai A, Nagamachi A, Inaba T.
    • Organizer
      第45回ISEH(国際実験血液学会)年次総会.
    • Place of Presentation
      米国 サンディエゴ
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 血中miRNA解析の標準化に関する基礎的検討 血漿と血清miRNA値の比較2016

    • Author(s)
      塩津 弘倫, 岡田 和大, 白濱 早紀, 黒木 千恵理, 上田 沙央理, 池田 勝義, 松井 啓隆, 栢森 裕三, 梅村 創
    • Organizer
      第63回臨床検査医学会学術集会
    • Place of Presentation
      神戸
    • Related Report
      2016 Annual Research Report
  • [Presentation] CYLDは頭頸部扁平上皮癌におけるEGFR標的治療の感受性制御因子である2016

    • Author(s)
      神力 悟, 城野 博丈, 安東 由喜雄, 松井 啓隆
    • Organizer
      第63回臨床検査医学会学術集会
    • Place of Presentation
      神戸
    • Related Report
      2016 Annual Research Report
  • [Presentation] 骨髄播種癌細胞の増殖抑制状態と抗癌剤耐性への細胞自律的制御機構の関与2015

    • Author(s)
      神力悟, 安東由喜雄, 松井啓隆
    • Organizer
      第62回日本臨床検査医学会学術集会
    • Place of Presentation
      岐阜
    • Year and Date
      2015-11-19
    • Related Report
      2015 Annual Research Report
  • [Presentation] 骨髄播種癌細胞が自律的に誘導する増殖抑制状態と抗癌剤耐性2015

    • Author(s)
      神力悟, 中村拓哉, 城野博史, 郭建莹, 瀬藤光利, 安東由喜雄, 松井啓隆
    • Organizer
      第55回日本臨床化学会年次学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2015-10-30
    • Related Report
      2015 Annual Research Report
  • [Presentation] Involvement of DDX41 p.R525H somatic mutation in the development of hypoplastic AML.2015

    • Author(s)
      Matsui H, Okuno M, Kanai A, Nagamachi A, Inaba T.
    • Organizer
      第77回 日本血液学会学術集会.
    • Place of Presentation
      金沢
    • Year and Date
      2015-10-18
    • Related Report
      2015 Annual Research Report
  • [Presentation] DDX41 p.R525H 体細胞変異による低形成白血病の発症メカニズム.2015

    • Author(s)
      松井啓隆, 奥野萌, 金井昭教, 長町安希子, 稲葉俊哉
    • Organizer
      第74回 日本癌学会学術集会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-10-10
    • Related Report
      2015 Annual Research Report
  • [Presentation] Defect in pre-ribosomal RNA processing is involved in myeloid leukemogenesis.2015

    • Author(s)
      Matsui H, Kanai A, Nagamachi A, Okuno M, Inaba T.
    • Organizer
      44th meeting of International Society of Experimental Hematology.
    • Place of Presentation
      京都
    • Year and Date
      2015-09-18
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Hematological malignancies harboring monosomy 7 as secondary diseases in irradiated patients.2015

    • Author(s)
      Matsui H, Nagamachi A, Kanai A, Inaba T.
    • Organizer
      15th meeting of International Congress of Radiation Research.
    • Place of Presentation
      京都
    • Year and Date
      2015-05-28
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Book] 造血器腫瘍アトラス 改訂第5版2016

    • Author(s)
      松井啓隆, 稲葉俊哉
    • Total Pages
      6
    • Publisher
      日本医事新報社
    • Related Report
      2016 Annual Research Report

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Published: 2015-04-16   Modified: 2018-03-28  

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