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Generating a cancer model using CRISPR/Cas9 system

Research Project

Project/Area Number 18K07205
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionKitasato University

Principal Investigator

Nagao Kazuaki  北里大学, 医学部, 講師 (60392487)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords母斑基底細胞癌症候群 / 髄芽腫 / 遺伝子編集 / PTCH1 / ヘッジホッグシグナル伝達系 / NBCCS / iPS細胞 / CRISPR/Cas9 / ゴーリン症候群 / ソニックヘッジホッグ / Gorlin / iPS
Outline of Final Research Achievements

Nevoid basal cell carcinoma syndrome (NBCCS), also called Gorlin syndrome, is an autosomal dominant disorder with an increased incidence of tumors. The PTCH1 gene, responsible for NBCCS, suppresses the hedgehog signaling pathway, which is recognized as one of the important pathways in tumorigenesis. We generated PTCH1-/- induced pluripotent stem cells (iPSCs) from NBCCS patient-derived iPSCs (PTCH1+/-) by gene editing. The proliferation of PTCH1-/- iPSCs was accelerated due to the activation of the hedgehog signaling pathway. When PTCH1-/- iPSCs were subcutaneously injected into immunodeficient mice, the resulting teratomas almost exclusively contained immature ectodermal lineage cells expressing medulloblastoma markers, and the percentages of the area occupied by medulloblastoma-like tissue were larger in PTCH1-/- teratomas than in PTCH1+/- teratomas. These results support the suitability of these gene-edited iPSCs and PTCH1-/- teratomas as models for the formation of tumors.

Academic Significance and Societal Importance of the Research Achievements

本研究は高発がん遺伝病患者由来細胞を用いて積極的にかつ部位特異的に遺伝子変異を導入することでがん化を誘導し、薬剤スクリーニングのモデル細胞として利用するという、世界的に見てもこれまでに例のない極めて独創的かつ斬新的なものである。本研究が進展し、効率よく細胞のがん化が誘導できようになればカウデン病、フォン・ヒッペル・リンドウ病などの他の高発がん遺伝病でも適用が可能であり、オーダーメイド医療の実践に向けて大きく前進するとともに、患者のQOL改善に大きく貢献できることが期待される研究である。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (5 results)

All 2019 2018

All Journal Article (1 results) (of which Peer Reviewed: 1 results) Presentation (4 results)

  • [Journal Article] Dysregulated DNA methylation of GLA gene was associated with dysfunction of autophagy2019

    • Author(s)
      Hiroko Yanagisawa, Mohammad Arif Hossaina, Takashi Miyajima, KazuakiNagao, Toshiyuki Miyashita, Yoshikatsu Eto
    • Journal Title

      Molecular Genetics and Metabolism

      Volume: 126 Issue: 4 Pages: 460-465

    • DOI

      10.1016/j.ymgme.2019.03.003

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] CRISPR/Cas9システムを用いたNBCCSモデルiPS細胞の作製2018

    • Author(s)
      長尾 和右、高山 吉永、宮下 俊之
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 母斑基底細胞癌症候群患者由来細胞を用いた腫瘍の作製2018

    • Author(s)
      長尾 和右、加藤 千勢、初瀬 洋美、高山 吉永、亀山 孝三、梅澤 明弘、藤井 克則、宮下 俊之
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] マウスのインプリンティング型X染色体不活化においてRNF12はREX1の抑制によって父由来non-coding RNA Tsix を抑制する2018

    • Author(s)
      中村 茜里、福田 篤、長尾 和右、阿久津 英憲、宮下 俊之
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 次世代シークエンサーを用いたGorlin症候群患者に発症した各種腫瘍の遺伝子解析2018

    • Author(s)
      兼友 裕大、高山 吉永、初瀬 洋美、藤谷 和子、長尾 和右、亀山 孝三、宮下 俊之
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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