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Identification of a novel drug target for rare disease using murine model of cystinosis

Research Project

Project/Area Number 17K07149
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Laboratory animal science
Research InstitutionNational Center for Global Health and Medicine

Principal Investigator

Okamura Tadashi  国立研究開発法人国立国際医療研究センター, その他部局等, 実験動物管理室長 (00333790)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords希少疾患 / マウス / シスチノーシス / 相関解析 / シスチン / 連鎖解析 / 量的形質遺伝子座解析 / 量的遺伝子座解析 / シスチン症
Outline of Final Research Achievements

Cystinosis is a rare progressive lysosomal storage disorder characterized by the accumulation of cystine in lysosomes, which is caused by a defect of cystine transporter called cystinosin (CTNS). It has been reported that renal dysfunction in Ctns deficient mice was dependent on their genetic background. The renal cystine levels of C57BL/6 Ctns deficient mice were much higher than those of FVB/N and the mixed 129Sv Ctns deficient mice. To clarify the genetic basis of cystine accumulation, we performed genetic association study using backcross progeny. A recessively acting locus responsible for the marked cystine accumulation (cysa) was mapped on mouse chromosome 12. The sequence analyses on the C57BL/6 and FVB/N genome detected a C57BL/6 specific variant leading stop gain within the cysa locus; the variant in Ahr was predicted to disrupt the protein function. Thus, Ahr is a potential candidate gene for the cysa locus. This will be the focus of future studies in both mice and humans.

Academic Significance and Societal Importance of the Research Achievements

希少疾患はこれまで、発症頻度の低さから数少ない患者を救済する慈善医療で、収益性がないと考えられていた。しかし、希少疾患研究から新たな分子創薬標的が発見され、「頻度が高い病気」(common disease)に対する新薬開発への手がかりを提供することがいくつかの疾患で示されている。本研究により、細胞内のシスチン蓄積とダイオキシンの受容体である芳香族炭化水素受容体遺伝子との関連が示唆され、新たな創薬標的となり得る可能性が示された。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (7 results)

All 2020 2019 2018 2017

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (3 results) (of which Invited: 1 results)

  • [Journal Article] Deletion of the Tensin2 SH2-PTB domain, but not the loss of its PTPase activity, induces podocyte injury in FVB/N mouse strain2020

    • Author(s)
      Sasaki Hayato、Takahashi Yuki、Ogawa Tsubasa、Hiura Koki、Nakano Kenta、Sugiyama Makoto、Okamura Tadashi、Sasaki Nobuya
    • Journal Title

      Experimental Animals

      Volume: 69 Issue: 2 Pages: 135-143

    • DOI

      10.1538/expanim.19-0101

    • NAID

      130007835074

    • ISSN
      0007-5124, 1341-1357, 1881-7122
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] d-Amino acid oxidase deficiency is caused by a large deletion in the Dao gene in LEA rats2020

    • Author(s)
      Shimizu Yukiko、Ishii Chiharu、Yanobu-Takanashi Rieko、Nakano Kenta、Imaike Akio、Mita Masashi、Hamase Kenji、Okamura Tadashi
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

      Volume: - Issue: 9 Pages: 140463-140463

    • DOI

      10.1016/j.bbapap.2020.140463

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic locus responsible for diabetic phenotype in the insulin hyposecretion (ihs) mouse2020

    • Author(s)
      Nakano Kenta、Yanobu-Takanashi Rieko、Shimizu Yukiko、Takahashi Yuki、Hiura Koki、Watanabe Masaki、Sasaki Hayato、Okamura Tadashi、Sasaki Nobuya
    • Journal Title

      PLOS ONE

      Volume: 15 Issue: 6 Pages: 234132-234132

    • DOI

      10.1371/journal.pone.0234132

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A deletion in the Ctns gene causes renal tubular dysfunction and cystine accumulation in LEA/Tohm rats2018

    • Author(s)
      Shimizu Yukiko、Yanobu-Takanashi Rieko、Nakano Kenta、Hamase Kenji、Shimizu Toshiaki、Okamura Tadashi
    • Journal Title

      Mammalian Genome

      Volume: 30 Issue: 1-2 Pages: 23-33

    • DOI

      10.1007/s00335-018-9790-3

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] ihsマウスのインスリン分泌不全原因遺伝子座の同定2019

    • Author(s)
      中野堅太、清水有紀子、佐々木隼人、安田千穂、高橋悠記、岡村匡史、佐々木宣哉
    • Organizer
      第66回日本実験動物学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] シスチノーシス確定診断法の確立2017

    • Author(s)
      大熊喜彰、清水有紀子、岡村匡史、赤平百絵、七野浩之
    • Organizer
      第120回日本小児科学会
    • Related Report
      2017 Research-status Report
  • [Presentation] CRISPR/Casシステムを用いた効率的遺伝子改変マウスの作製とその応用2017

    • Author(s)
      岡村匡史
    • Organizer
      第28回東北実験動物研究会
    • Related Report
      2017 Research-status Report
    • Invited

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Published: 2017-04-28   Modified: 2021-02-19  

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