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2012 Fiscal Year Annual Research Report

ヒトES/iPS細胞を用いた先天性遺伝性疾患の病態解析と新規治療法の開発

Research Project

Project/Area Number 22249042
Research InstitutionKyoto University

Principal Investigator

中畑 龍俊  京都大学, iPS細胞研究所, 特定拠点教授 (20110744)

Co-Investigator(Kenkyū-buntansha) 斎藤 潤  京都大学, iPS細胞研究所, 准教授 (90535486)
丹羽 明  京都大学, iPS細胞研究所, 助教 (20546999)
大嶋 宏一  京都大学, iPS細胞研究所, 研究員 (60525377)
Project Period (FY) 2010-04-01 – 2013-03-31
Keywords遺伝性疾患 / iPS細胞 / 遺伝子改変 / 疾患解析 / NOGマウス / 疾患特異的 / 創薬
Research Abstract

遺伝性疾患を持つ患者の皮膚や血液より誘導したiPS細胞(疾患特異的iPS細胞)は、患部を含むすべての組織に分化可能なことから、その疾患の病態解析や創薬、治療法開発に極めて有用であると考えられる。
本研究では、疾患特異的iPS細胞の標準化を行うとともに、種々の細胞系列への適切な細胞の分化系を構築しその応用により、各種遺伝性疾患のiPS細胞を用いた病態解析を行い、今まで知られていなかった新たな知見を得ることを目的として行われた。
Kostmann 症候群、Chediak-東症候群(CHS)、CINCA 症候群、脊髄性萎縮性筋委縮症(SMA)などの患者からiPS細胞を樹立し、病態解析を行った。一方、Fanconi 貧血、細網異形成症患者からは通常の方法ではiPS細胞は樹立できなかったためエピゾーマルベクターを用いて線維芽細胞段階で一過性に遺伝子を修復後、iPS細胞の樹立を試み成功した。樹立されたiPS細胞の機能解析を行うため、様々な細胞系列への分化系を構築した。血球系においては造血発生過程を反映すると共に正常な機能を持った血球として赤血球、好中球、巨核球、単球・マクロファージ・樹状細胞、Tリンパ球、マスト細胞等様々な細胞に分化できることが確認された。体細胞モザイクでCIAS1遺伝子異常を持つCINCA症候群の患者からwild typeとmutant typeの両方のiPS細胞が樹立され、両者から分化させた単球・マクロファージの機能の違いの解析が行われた。変異NLRP3を持つ細胞のみがLPS単独刺激で過剰なIL-1bを産生するという特徴的な表現型を示すことを確認した。この細胞を用いて、新規NLRP3インフラマソーム抑制薬をスクリーニングするための実験系を構築した。CHSにおける好中球の巨大顆粒、SMAでは運動神経の危弱性などiPS細胞由来の細胞における表現型が確認された。

Current Status of Research Progress
Reason

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

  • Research Products

    (43 results)

All 2013 2012

All Journal Article (16 results) (of which Peer Reviewed: 13 results) Presentation (27 results) (of which Invited: 4 results)

  • [Journal Article] Recipient seropositivity for adenovirus type 11 is highly predictive of the development of hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.2013

    • Author(s)
      Nakazawa Y.
    • Journal Title

      Bone Marrow Transplant.

      Volume: in press Pages: in press

    • Peer Reviewed
  • [Journal Article] Clonal selection in xenografted TAM recapitulatesthe evolutionary process of myeloid leukemia in Down syndrome.2013

    • Author(s)
      Saida S.
    • Journal Title

      Blood

      Volume: in press Pages: in press

    • Peer Reviewed
  • [Journal Article] 疾患特異的iPS細胞2013

    • Author(s)
      斎藤潤
    • Journal Title

      再生医療

      Volume: 12 Pages: 19-29

  • [Journal Article] The CD40-CD40L axis and INF-g play critical roles in Langerhans giant cell formation.2012

    • Author(s)
      Sakai H.
    • Journal Title

      Int. Immunol.

      Volume: 24 Pages: 5-15

    • Peer Reviewed
  • [Journal Article] Detection of base substitution–type somatic mosaicism of the NLRP3 gene with >99.9% statistical confidence by massively parallel sequencing.2012

    • Author(s)
      IzawaK.
    • Journal Title

      DNA Res.

      Volume: 19 Pages: 143-152

    • Peer Reviewed
  • [Journal Article] Pediatric idiopathic TTP diagnosed with decreased ADAMTS13 activity.2012

    • Author(s)
      Morishima T.
    • Journal Title

      Pediatr. Int.

      Volume: 54 Pages: 422-423

    • Peer Reviewed
  • [Journal Article] Increased susceptibility to severe chronic liver damage in CXCR4 conditional knock-out mice.2012

    • Author(s)
      Tsuchiya A.
    • Journal Title

      Dig. Dis. Sci.

      Volume: 57 Pages: 2892-2900

    • DOI

      10.1007/s10620-012-2239-8

    • Peer Reviewed
  • [Journal Article] Acut liver failure in young children with systemic-onset juvenile idiopathic arthritis without macrophage activation syndrome: Report of two cases.2012

    • Author(s)
      Hiejima E.
    • Journal Title

      J. Pediatr. Child Health

      Volume: 48 Pages: E122-125

    • Peer Reviewed
  • [Journal Article] Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia and immunodeficiency.2012

    • Author(s)
      Kawai T.
    • Journal Title

      Blood

      Volume: 119 Pages: 5458-5466

    • Peer Reviewed
  • [Journal Article] Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease.2012

    • Author(s)
      Tsumura M.
    • Journal Title

      Human Mutation Human Mutation

      Volume: 33 Pages: 1377-1387

    • DOI

      10.1002/humu.22113

    • Peer Reviewed
  • [Journal Article] Outcome of children with Refractory Anaemia with Excess of Blast (RAEB) and RAEB in Transformation (RAEB-T) in the Japanese MDS99 study.2012

    • Author(s)
      Kikuchi A.
    • Journal Title

      Brit. J. Haematol.

      Volume: 158 Pages: 657-661

    • DOI

      10.1111/j.1365-2141.2012.09210.x

    • Peer Reviewed
  • [Journal Article] Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery.2012

    • Author(s)
      Tanaka T.
    • Journal Title

      Blood

      Volume: 120 Pages: 1299-1308

    • Peer Reviewed
  • [Journal Article] Drug screening for ALS using patient-specific induced pluripotent stem cells.2012

    • Author(s)
      Egawa N.
    • Journal Title

      Sci Transl Med.

      Volume: 1 Pages: 145ra104

    • Peer Reviewed
  • [Journal Article] Multiple reversions of an IL2RG mutation restore combined immunodeficiency patient.2012

    • Author(s)
      Kawai T.
    • Journal Title

      J. Clin. Immunol.

      Volume: 32 Pages: 690-697

    • Peer Reviewed
  • [Journal Article] 白血病治療の進歩と今後の展望2012

    • Author(s)
      中畑龍俊
    • Journal Title

      日本小児血液・がん学会雑誌

      Volume: 49 Pages: 11-15

  • [Journal Article] 幹細胞増幅2012

    • Author(s)
      中畑龍俊
    • Journal Title

      カラー版内科学

      Volume: 総編集 Pages: 447-450

  • [Presentation] Excess reduction of anthracyclines results in inferior event-free survival in core binding factor acute myeloid leukemia in children; A report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)2012

    • Author(s)
      Tomizawa D.
    • Organizer
      54th Annual Meeting of the AMERICAN SOCIETY of HEMATOLOGY
    • Place of Presentation
      GeorGia World ConGress Center,Atlanta
    • Year and Date
      20121208-20121211
  • [Presentation] Mesodermal development from reprogrammed Fanconi anemia cells is affected by ALDH2 enzymatic activity.2012

    • Author(s)
      Suzuki N.
    • Organizer
      54th Annual Meeting of the AMERICAN SOCIETY of HEMATOLOGY
    • Place of Presentation
      GeorGia World ConGress Center,Atlanta
    • Year and Date
      20121208-20121211
  • [Presentation] Immunosuppressive therapy with antithymocyte globulin and Cyclosporine for fulminant aplastic anemia.2012

    • Author(s)
      Yagasaki H.
    • Organizer
      54th Annual Meeting of the AMERICAN SOCIETY of HEMATOLOGY
    • Place of Presentation
      GeorGia World ConGress Center,Atlanta
    • Year and Date
      20121208-20121211
  • [Presentation] Appropriate dose modification in induction therapy is essential for the treatment of infants with acute myeloid leukemia; A report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)2012

    • Author(s)
      Tomizawa D.
    • Organizer
      54th Annual Meeting of the AMERICAN SOCIETY of HEMATOLOGY
    • Place of Presentation
      GeorGia World ConGress Center,Atlanta
    • Year and Date
      20121208-20121211
  • [Presentation] Attempts to optimize post-induction treatment in childhood acute myeloid leukemia without core binding factors: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)2012

    • Author(s)
      Hasegawa D.
    • Organizer
      54th Annual Meeting of the AMERICAN SOCIETY of HEMATOLOGY
    • Place of Presentation
      GeorGia World ConGress Center,Atlanta
    • Year and Date
      20121208-20121211
  • [Presentation] 経過中に急性転化したJMML23例の検討;MDS委員会のデータベースから2012

    • Author(s)
      本田裕子
    • Organizer
      第54回日本小児血液・がん学会学術集会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      20121130-20121202
  • [Presentation] NOGマウスを用いたTAMの病態解析2012

    • Author(s)
      才田聡
    • Organizer
      第54回日本小児血液・がん学会学術集会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      20121130-20121202
  • [Presentation] Treatment outcome of refractory cytopenia of childhood(RCC):A prospective registration through the Japanese Society of Pediatric Hematology/Oncology(JSPHO) between 1999 and 2008.2012

    • Author(s)
      Hasegawa D
    • Organizer
      第54回日本小児血液・がん学会学術集会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      20121130-20121202
  • [Presentation] Outcome of Immunousuppressive therapy in children with fulminant aplastic anemia.2012

    • Author(s)
      Yagasaki H
    • Organizer
      第54回日本小児血液・がん学会学術集会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      20121130-20121202
  • [Presentation] iPS細胞研究の進展2012

    • Author(s)
      中畑龍俊
    • Organizer
      第59回日本臨床検査医学会学術集会
    • Place of Presentation
      国立京都国際会館
    • Year and Date
      20121129-20131202
    • Invited
  • [Presentation] Long-term follow-up of more than 545 chilren with myelodysplastic syndrome (MDS) and myeloproliferative neoplasms(MPN)2012

    • Author(s)
      Manabe A
    • Organizer
      VI Internatonal Symposium on Myelodysplastic Syndoromes and Bone Marrow Failures in Childhood
    • Place of Presentation
      Diplomat Hotel,Prague
    • Year and Date
      20121107-20121109
  • [Presentation] Clinic characteristics of 23 children with juvenile myelomonocytic leukemia who developed blast crisis: MDS Committee of LSPHO2012

    • Author(s)
      Honda Y
    • Organizer
      VI Internatonal Symposium on Myelodysplastic Syndoromes and Bone Marrow Failures in Childhood
    • Place of Presentation
      Diplomat Hotel,Prague
    • Year and Date
      20121107-20121109
  • [Presentation] Treatment outcome of 67 cases with refractory cytopenia of childhood(RCC): A Prostective Registration Through The Japanese Society of Pediatric Hematology/Oncology(JSPHO)2012

    • Author(s)
      Hasegawa D
    • Organizer
      VI Internatonal Symposium on Myelodysplastic Syndoromes and Bone Marrow Failures in Childhood
    • Place of Presentation
      Diplomat Hotel,Prague
    • Year and Date
      20121107-20121109
  • [Presentation] 小児患者におけるiPS細胞の応用2012

    • Author(s)
      中畑龍俊
    • Organizer
      第49回日本小児アレルギー学会
    • Place of Presentation
      大阪国際会議場
    • Year and Date
      20120915-20120916
    • Invited
  • [Presentation] iPS細胞から単球・樹状細胞の分化誘導と疾患iPS細胞研究への応用2012

    • Author(s)
      柳町昌克
    • Organizer
      第5回自己炎症疾患研究会
    • Place of Presentation
      福岡朝日ビル
    • Year and Date
      20120706-20120706
  • [Presentation] 表面マーカーによる初期化成功予測因子の解析2012

    • Author(s)
      川村晃久
    • Organizer
      第33回日本炎症・再生医学会
    • Place of Presentation
      ホテル日航福岡
    • Year and Date
      20120705-20120706
  • [Presentation] 初期化誘導過程で出現する心筋前駆様細胞を用いた安全かつ効率的な心筋再生療法の確立2012

    • Author(s)
      川村晃久
    • Organizer
      第33回日本炎症・再生医学会
    • Place of Presentation
      ホテル日航福岡
    • Year and Date
      20120705-20120706
  • [Presentation] CINCA症候群におけるNLRP3体細胞モザイク変異2012

    • Author(s)
      井澤和司
    • Organizer
      第33回日本炎症・再生医学会
    • Place of Presentation
      ホテル日航福岡
    • Year and Date
      20120705-20120706
  • [Presentation] Differentiation of monocytic lineage cells from human iPS cells by using a serum and feeder free culture method.2012

    • Author(s)
      Yanagimachi M
    • Organizer
      10th Annual Meeting of International Society for Stem Cell Research (ISSCR)
    • Place of Presentation
      Pacifico Yokohama
    • Year and Date
      20120613-20120616
  • [Presentation] Human ESC/IPSC-Derived mesenchymal stroma can support hematopoietic progenitors.2012

    • Author(s)
      Niwa A.
    • Organizer
      10th Annual Meeting of International Society for Stem Cell Research (ISSCR)
    • Place of Presentation
      Pacifico Yokohama
    • Year and Date
      20120613-20120616
  • [Presentation] Induced pluripotent stem cell model of severe congenital neutropenia with HAX1 gene deficiency.2012

    • Author(s)
      Morishima T
    • Organizer
      10th Annual Meeting of International Society for Stem Cell Research (ISSCR)
    • Place of Presentation
      Pacifico Yokohama
    • Year and Date
      20120613-20120616
  • [Presentation] Understanding the pathology of the arthropathy in chronic infantile neurological cutaneous and articular syndrome by using iPS cells technology.2012

    • Author(s)
      Yokoyama K
    • Organizer
      10th Annual Meeting of International Society for Stem Cell Research (ISSCR)
    • Place of Presentation
      Pacifico Yokohama
    • Year and Date
      20120613-20120616
  • [Presentation] Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery.2012

    • Author(s)
      Tanaka T
    • Organizer
      10th Annual Meeting of International Society for Stem Cell Research (ISSCR)
    • Place of Presentation
      Pacifico Yokohama
    • Year and Date
      20120613-20120616
  • [Presentation] iPS細胞を用いたこれからの小児医療の可能性2012

    • Author(s)
      中畑龍俊
    • Organizer
      旭川小児科医会講演会
    • Place of Presentation
      旭川ロワジールホテル
    • Year and Date
      20120515-20120515
    • Invited
  • [Presentation] iPS細胞研究の今、その可能性と将来展望2012

    • Author(s)
      中畑龍俊
    • Organizer
      第115回日本小児科学学術集会
    • Place of Presentation
      福岡国際会議場
    • Year and Date
      20120420-20120422
    • Invited
  • [Presentation] 次世代シーケンサーによるNLRP3体制モザイクの診断2012

    • Author(s)
      井澤和司
    • Organizer
      第115回日本小児科学学術集会
    • Place of Presentation
      福岡国際会議場
    • Year and Date
      20120420-20120422
  • [Presentation] 白血球減少、骨髄異形成とリンパ浮腫を呈するGATA-2異常2012

    • Author(s)
      石田宏之
    • Organizer
      第115回日本小児科学学術集会
    • Place of Presentation
      福岡国際会議場
    • Year and Date
      20120420-20120422

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Published: 2014-07-24  

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