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Analysis of disease mechanism and discovery of novel treatment for neurofibromatosis type 2 using patient-derived induced pluripotent stem cell

Research Project

Project/Area Number 19K09519
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56010:Neurosurgery-related
Research InstitutionHokkaido University

Principal Investigator

Shunsuke Terasaka  北海道大学, 医学研究院, 客員研究員 (10447055)

Co-Investigator(Kenkyū-buntansha) 江良 択実  熊本大学, 発生医学研究所, 教授 (00273706)
伊師 雪友  北海道大学, 医学研究院, 客員研究員 (30812284)
小林 浩之  北海道大学, 医学研究院, 客員研究員 (70374478)
山口 秀  北海道大学, 大学病院, 講師 (70399939)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords神経線維腫症2型 / NF2 / iPS細胞 / 人工多能性幹細胞 / Schwann細胞 / neurofibromatosis type 2 / 疾患特異的iPS細胞 / 神経鞘腫
Outline of Research at the Start

神経線維腫症2型(neurofibromatosis type2, NF2)はNF2遺伝子の異常に起因する常染色体優性遺伝疾患である。頭蓋内外の神経鞘腫や髄膜腫、上衣腫などが多発し、有効な内科的治療が存在せず新規の薬剤治療が望まれる。本研究ではNF2の患者から誘導したiPSCを用いて神経鞘腫モデルの樹立を行い、NF2における神経鞘腫に対する新規標的治療の開発を目指す。

Outline of Final Research Achievements

We established patient-derived iPS cell using peripheral blood mononuclear cells harvested from 5 patients with neurofibromatosis type 2 (NF2). Expression of stem cell markers were observed in all of established iPSC lines. In a case with NF2 mosaicism, presence or absence of NF2 mutation differed between iPSC clones, while expression of genes in pathways associated with NF2 gene were not different between these iPSC clones, which suggested that biallelic inactivation of NF2 is necessary for tumorigenesis in NF2 patient. We tried to establish in vitro model of schwannoma by differentiation induction for shcwann cell, but it was failed to differentiate neural crest to schwann cell using iPSC derived from healthy human.

Academic Significance and Societal Importance of the Research Achievements

本研究では神経線維腫症2型(NF2)患者由来iPS細胞株の樹立を行った。体細胞モザイクの症例から樹立したiPS細胞ではNF2遺伝子の変異の有無がクローン毎に異なりドナーにおける遺伝子変異の分布が受け継がれていると考えられた。しかしNF2遺伝子に関連したシグナル経路の遺伝子発現はクローン間で差を認めず、NF2遺伝子の両側アレルの機能不活性化が、腫瘍発生に必須であることが示された。今後はシュワン細胞への分化誘導条件を検討することで、NF2における腫瘍発生のメカニズムや新規治療法を探索するためのソースとなりうる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (2 results)

All 2022 2021

All Journal Article (2 results) (of which Peer Reviewed: 1 results)

  • [Journal Article] Analysis of induced pluripotent stem cell clones derived from a patient with mosaic neurofibromatosis type 22022

    • Author(s)
      Ishi Yukitomo、Era Takumi、Yuzawa Sayaka、Okamoto Michinari、Sawaya Ryosuke、Motegi Hiroaki、Yamaguchi Shigeru、Terasaka Shunsuke、Houkin Kiyohiro、Fujimura Miki
    • Journal Title

      American Journal of Medical Genetics Part A

      Volume: - Issue: 6 Pages: 1863-1867

    • DOI

      10.1002/ajmg.a.62700

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Variations and natural history of primary intraparenchymal lesions associated with neurofibromatosis type 22021

    • Author(s)
      Ishi Yukitomo、Harada Taisuke、Kameda Hiroyuki、Okada Hiromi、Yokota Isao、Okamoto Michinari、Sawaya Ryosuke、Motegi Hiroaki、Yamaguchi Shigeru、Terasaka Shunsuke、Kudo Kohsuke、Fujimura Miki
    • Journal Title

      Neuroradiology

      Volume: 64 Issue: 2 Pages: 393-396

    • DOI

      10.1007/s00234-021-02809-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed

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Published: 2019-04-18   Modified: 2023-01-30  

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