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Hedgehog signaling in human diseases

Research Project

Project/Area Number 16K09960
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionChiba University

Principal Investigator

FUJII KATSUNORI  千葉大学, 大学院医学研究院, 講師 (70344992)

Co-Investigator(Kenkyū-buntansha) 宮下 俊之  北里大学, 医学部, 教授 (60174182)
梅澤 明弘  国立研究開発法人国立成育医療研究センター, 再生医療センター, 副所長/再生医療センター長 (70213486)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsヘッジホッグ / Gorlin症候群 / 基底細胞母斑症候群 / 基底細胞癌 / 髄芽腫 / 皮膚線維芽細胞 / iPS細胞 / ヘッジホッグシグナル / ゴーリン症候群 / PTCH1 / 高発癌性疾患 / シグナル伝達 / 脳神経疾患 / 再生医学 / 遺伝学 / ゲノム
Outline of Final Research Achievements

The hedgehog signaling pathway is a vital factor for embryonic development and stem cell maintenance. Dysregulation of its function results in tumor initiation and progression. The aim of this research was to establish a disease model of hedgehog-related tumorigenesis with Gorlin syndrome-derived induced pluripotent stem cells (GS-iPSCs). Induced neural progenitor cells from GS-iPSCs (GS-NPCs) shows constitutive high GLI1 expression and higher sensitivity to smoothened (SMO) inhibition compared to wild-type induced neural progenitor cells (WT-NPCs). The differentiation process from iPSCs to NPCs may have similarity in gene expression to Hedgehog signal related-carcinogenesis. Therefore, GS-NPCs may be useful for screening compounds to find effective drugs to control Hedgehog signaling activity.

Academic Significance and Societal Importance of the Research Achievements

本研究では、世界初のGorlin症候群iPS細胞を作製し、ヘッジホッグシグナルの発生段階での特性を解明したことは大きな学術的成果といえる。特にGorlin iPS細胞を分化誘導させることで、未分化な状態から神経分化に移行した時点でヘッジホッグシグナルが最も亢進し阻害剤が効果的に働くこと、また遺伝子変異がある場合には亢進が持続して癌化に至ることが解明したことは、個体が発生から組織分化する過程でヘッジホッグ経路を始めとした多様なシグナル系が選択的に活性化されることを示した点で興味深い。本研究でGorlin症候群由来のiPS細胞はヘッジホッグシグナル異常症の疾患モデルとして有用であることが示された。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (15 results)

All 2019 2018 2017 Other

All Journal Article (6 results) (of which Peer Reviewed: 5 results,  Open Access: 4 results,  Acknowledgement Compliant: 3 results) Presentation (6 results) Remarks (3 results)

  • [Journal Article] Gorlin症候群の遺伝子診断2019

    • Author(s)
      宮下俊之、高山吉永
    • Journal Title

      医学のあゆみ

      Volume: 268 Pages: 123-126

    • Related Report
      2018 Annual Research Report
  • [Journal Article] MicroRNAs profiling in fibroblasts derived from patients with Gorlinsyndrome2019

    • Author(s)
      Shiohama T., Fujii K., Miyashita T., Takatani T., Ikehara H., Uchikawa H., Motojima T., Uchida T, Shimojo N
    • Journal Title

      Journal of Human Genetics

      Volume: -

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel PTCH1 mutation in basal cell nevus syndrome with rare craniofacial features2019

    • Author(s)
      Murata Y, Kurosaka H, Ohata Y, Aikawa T, Takahata S, Fujii K, Miyashita T, Morita C, Inubushi T, Kubota T, Sakai N, Ozono K, Kogo M, Yamashiro T.
    • Journal Title

      Human Genome Variation

      Volume: 6 Issue: 1 Pages: 16-16

    • DOI

      10.1038/s41439-019-0047-9

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nevoid basal cell carcinoma syndrome caused by splicing mutations in the PTCH1 gene.2017

    • Author(s)
      Kato, C., Fujii, K., Arai, Y., Hatsuse, H., Nagao, K., Takayama, Y., Kameyama, K., Fujii, K., and Miyashita, T.
    • Journal Title

      Familial Cancer

      Volume: 16 Issue: 1 Pages: 131-138

    • DOI

      10.1007/s10689-016-9924-2

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Brain morphology in children with nevoid basal cell carcinoma syndrome.2017

    • Author(s)
      Shiohama, T., Fuji, K., Miyashita, T., Mizuochi, H., Uchikawa, H., Shimojo, N.
    • Journal Title

      American Journal of Medical Genetics A

      Volume: 173 Issue: 4 Pages: 946-952

    • DOI

      10.1002/ajmg.a.38115

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Somatic mosaicism containing double mutations in PTCH1 revealed by generation of induced pluripotent stem cells from nevoid basal cell carcinoma syndrome.2017

    • Author(s)
      Ikemoto, Y., Takayama, Y., Fujii, K., Masuda, M., Kato, C., Hatsuse, H., Fujitani, K., Nagao, K., Kameyama, K., Ikehara, H., Toyoda, M., Umezawa, A. and Miyashita, T.
    • Journal Title

      Journal of Medical Genetics

      Volume: - Issue: 8 Pages: 579-584

    • DOI

      10.1136/jmedgenet-2016-104490

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [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 Annual Research Report
  • [Presentation] MicroRNA analysis in dermal fibroblasts derived from Gorlin syndrome patients2017

    • Author(s)
      Shiohama, T. Fujii, K. Takatani, T. Miyashita, T. Ikehara, H. Fujita, M. Fukuhara, T. Shimojo, N.
    • Organizer
      第59回日本小児神経学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 疾患特異的iPS細胞の解析を契機に発見された母斑基底細胞癌症候群のモザイク症例2017

    • Author(s)
      宮下 俊之、高山吉永、藤井 克則、梅澤 明弘
    • Organizer
      第23回日本家族性腫瘍学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 母斑基底細胞癌症候群患者由来のiPS細胞に見いだされたPTCH1遺伝子の体細胞モザイク変異2017

    • Author(s)
      高山吉永、長尾 和右、宮下 俊之、藤井 克則
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Gorlin症候群責任遺伝子PTCH1のディープシークエンス解析2017

    • Author(s)
      増田 木理、兼友裕大、高山吉永、初瀬洋美、藤谷和子、長尾 和右、亀山 孝三、藤井 克則、宮下 俊之
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] CRISPR/Cas9システムを用いたNBCCS疾患モデルiPS細胞の作製2017

    • Author(s)
      荒井佑斗、加藤千勢、長尾和右、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40回日本分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Remarks] 千葉大学大学院医学研究院小児病態学神経グループ

    • URL

      http://www.m.chiba-u.jp/dept/pediatrics/research/group/nerve/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 千葉大学小児科 神経グループ

    • URL

      https://www.pediatrics-chiba-u.org/research/group_nerve.html

    • Related Report
      2017 Research-status Report
  • [Remarks] 千葉大学小児病態学神経グループ

    • URL

      http://www.pediatrics-chiba-u.org/research/group_nerve.html

    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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