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正常骨髄造血幹細胞への試験管内遺伝子導入による免疫細胞調節遺伝子の研究

Research Project

Project/Area Number 04253236
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Research InstitutionKyoto University (1993)
Kumamoto University (1992)

Principal Investigator

西川 伸一 (西信 伸一)  京都大学, 医学部, 教授 (60127115)

Project Period (FY) 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥12,900,000 (Direct Cost: ¥12,900,000)
Fiscal Year 1993: ¥8,900,000 (Direct Cost: ¥8,900,000)
Fiscal Year 1992: ¥4,000,000 (Direct Cost: ¥4,000,000)
Keywords長期骨髄培養 / 幹細胞 / 遺伝子導入 / c-kit / RARの遺伝子 / 白血病 / 長期骨髄細胞培養 / レトロビールスベクター / ストローマ細胞 / SCF / 造血幹細胞
Research Abstract

この研究の目的は、長期骨髄細胞培養系で増殖している幹細胞の遺伝子操作を行なうことである。昨年度の研究で、効率の高い遺伝子導入方法を確立しており、この方法の有効性を調べる目的で本年はPML-RAR融合遺伝子の骨髄幹細胞への導入を試みた。しかし、この融合遺伝子を正常な形で発現しているビールス粒子を得ることが出来ず、この方法の問題点が明らかになった。
一方、この実験の一環として行なっていたRAR遺伝子の導入実験から、RAR遺伝子の過剰発現で、顆粒球系細胞の分化の抑制が起こることが明らかになり、急性前顆粒球性白血病の形質の一部がRAR遺伝子の過剰発現で説明できることを明らかに出来た。このことは、特に毒性の強い遺伝子でなければ我々の方法で長期骨髄培養への遺伝子導入が可能であること、及び増殖に対して抑制効果がある遺伝子でも、場合によってはその造血細胞に対する影響を調べることが可能であることを示した。
幹細胞操作には、幹細胞特異的に遺伝子を発現出来るプロモーター領域の開発が必要であるが、我々はこの目的でc-kit遺伝子調節領域について研究した。この遺伝子の上流域は、遺伝子発現に対して抑制的であることをこれまで明らかにしていたので、本年度はこの抑制を組織特異的に解除する領域について検索した。現在、第一イントロン内に造血細胞及びライディッヒ細胞でこの抑制を外すが、c-kit陰性の細胞では影響が内領域を突き止めることが出来た。この領域について、今後はトランスジェニックマウスの技術を用いて個体レベルで検討する予定である。

Report

(2 results)
  • 1993 Annual Research Report
  • 1992 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Matsuzaki Y.: "Characterization of c-kit positive intrathymic stem cells that are restricted to lymphoid differentiation." J.Exp.Med.178. 9125-9129 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Sudo T.: "Expression and function of interleukin-7 receptor in murine lymphocytes." Proc.Natl.Acad.Sci.USA. 90. 9125-9129 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Takahashi K.: "Differentiation of dendritic cell populations in macrophage colony stimulating factor-defocoent mice homozygous for the osteopetrosis mutation." J.Leuk.Biology. 53. 19-28 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Lev S.: "Interspecies molecular chimeras of kit help define the binding site of the stem cell factor." Mol.Cell.Biology. 13. 2224-2234 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Ogawa M.: "Expression and function of c-kit in fetal hemopoietic progenitor cells:transition from the early c-kit-independent to the late c-kit-dependent wave of hemopoiesis in the murine embryo." Development. 117. 1089-1098 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] T.Era: "How B-Precursor cells are driven to cycle" Immunological Reviews. 137(now printing). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Ogawa M.: "Acad Press.Inc.Tokyo" Cellular and molecular requirement for hemtopoietic microenvironment.in ″Molecular Basis of Immune Response″, 287 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] M.Takagi: "Stimulation of mouse connective tissve type mast cells by hemopoietic stem cell factor,a ligana for the c-kit receptor." J.Immunol. 148. 3446-3453 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] H.Kodama: "In vitro proliferation of primitive hemopoietic stem cells supporterd by stromal cells:evidence for the presence of a mechanism(s)other that involving c-kit receptor and its ligand." J.Exp.Med.176. 351-362 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] R.Palacios: "Developmentaly regulated cell surface expression and function of c-kit receptor during lymphocyte ontogeny in the embryo and adult mice." Development. 115. 1133-1147 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] SI.Nishikawa: "Ichain expression of B cells generated in vitro:Desire for immaculate virgin B-cell." Res.Immunol.143. 818-821 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Y.Edi: "Low c-kit expression of cultured mast cells of mi/mi genotype may be involved in their defective response to fibroblasts tha express the ligand for c-kit." Blood. 80. 1454-1460 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] SI.Nishikawa: "Control of intramarrow B cell-genesis by stromal cell derived mole cules." Cuir.Topics Immunol.182. 27-35 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] H.Maeda: "Reguirement of c-kit for development of intestinal Pacemaker system." Development. 116. 369-375 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] J.Kanemoto: "Balb/3T3 fibroblast-conditioned medium attracts caltured mast cells derived from W/W butnot from mi/mi mice both of whith are dificient in mast cells." Blood. 80. 1933-1939 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] T.Tono: "C-kit gene was not transcribed in cultured mast cells of mast cell-deficient W^<sh>/W^<sh> mice that have a monal mumber of erythrocytes and a nomal c-kit coding region." Blood. 80. 1448-1453 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] N.Miki: "Role of I-A molecules in early stages of B cell maturation." J.Immunol.149. 801-807 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] H.Takeda: "Expression of c-kit,a proto-Oncogene of the murine w locus,in cerebella of normal and neuroloucal mutant mice:Immunohistochemi cal and in situ hibridization analysis." Differentiation. 51. 121-127 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] M.Ogawa: "Expression and function of c-kit in fetal hemopoietic grogenitor cells:transition from the early c-kit-indeprndent to the late c-kit-dependent wave of hemopoiesis." Development. 117. (1993)

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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