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Generation of human urate metabolism complete model mice by suppressing xanthine dehydrogenase expression

Research Project

Project/Area Number 17K08605
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General pharmacology
Research InstitutionTeikyo University

Principal Investigator

Hosoyamada Makoto  帝京大学, 薬学部, 教授 (00291659)

Co-Investigator(Kenkyū-buntansha) 富岡 直子  帝京大学, 薬学部, 講師 (60525814)
金子 希代子  帝京大学, 薬学部, 教授 (90147075)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsキサンチンオキシドレダクターゼ / ウリカーゼ / ヒポキサンチンホスホリボシルトランスフェラーゼ / 酵素 / 核酸
Outline of Final Research Achievements

We tried to create human urate metabolism complete model mice by uricase (Uox) deletion, hypoxanthine phosphoribosyl transferase (HPRT) high activity, and suppression of xanthine oxidoreductase (XOR) expression.
As a result, two strains of HPRT highly active Uox-Xor-double knockout mouse-human XOR transgenic mice having different human XOR expression levels were obtained. Although urinary hypoxanthine and xanthine excretion remained in both strains and blood creatinine was elevated and showed renal damage in a strain with low human XOR activity, but in a strain with high human XOR activity, blood creatinine was not elevated, In summary, human uric acid metabolism complete model mice that do not cause renal damage were obtained.

Academic Significance and Societal Importance of the Research Achievements

学術的意義は3つの遺伝子発現をヒト化することによりプリン代謝の分野で初めてヒトの病態を反映する疾患モデル動物が得られた点である。社会的意義は、(1)環境要因に伴う高尿酸血症の発症メカニズム解明が可能となり、生活習慣病の新薬開発に繋がる。(2) 家族性若年性高尿酸性血症性腎症や腎性低尿酸血症のモデルマウスの作出により、治療法の無い尿酸関連遺伝性疾患の治療薬開発に結びつく。(3)すべての研究用マウスはHPRT低活性でレッシュ=ナイハン症候群様であることから、高次脳機能の研究のためにHPRT高活性ヒトXDH低発現マウスが有用となる。

Report

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

    (15 results)

All 2020 2019 2018 2017

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (8 results) (of which Int'l Joint Research: 2 results) Patent(Industrial Property Rights) (3 results)

  • [Journal Article] Perfecting a high hypoxanthine phosphoribosyltransferase activity–uricase KO mice to test the effects of purine- and non-purine-type xanthine dehydrogenase (XDH) inhibitors2020

    • Author(s)
      Hosoya T, Uchida S, Shibata S, Tomioka NH, Hosoyamada M.
    • Journal Title

      Br J Pharmacol.

      Volume: 177 Issue: 10 Pages: 2274

    • DOI

      10.1111/bph.14978

    • URL

      https://pure.teikyo.jp/en/publications/26947633-9b21-466b-9462-d8607e91715f

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Renoprotective effect of topiroxostat via antioxidant activity in puromycin aminonucleoside nephrosis rats2017

    • Author(s)
      Kawamorita Y, Shiraishi T, Tamura Y, Kumagai T, Shibata S, Fujigaki Y, Hosoyamada M, Nakagawa T, Uchida S.
    • Journal Title

      Physiological reports

      Volume: 5 Issue: 15 Pages: e13358-e13358

    • DOI

      10.14814/phy2.13358

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Insulin stimulates uric acid reabsorption via regulating urate transporter 1 and ATP-binding cassette subfamily G member 22017

    • Author(s)
      Toyoki D, Shibata S, Kuribayashi-Okuma E, Xu N, Ishizawa K, Hosoyamada M, Uchida S.
    • Journal Title

      American journal of physiology. Renal physiology.

      Volume: 313 Issue: 3 Pages: 826-834

    • DOI

      10.1152/ajprenal.00012.2017

    • URL

      https://pure.teikyo.jp/en/publications/d06c4a71-34cf-4f10-975e-deddfb7da550

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Podocyte Injury and Albuminuria in Experimental Hyperuricemic Model Rats2017

    • Author(s)
      Asakawa S, Shibata S, Morimoto C, Shiraishi T, Nakamura T, Tamura Y, Kumagai T, Hosoyamada M, Uchida S.
    • Journal Title

      Oxid Med Cell Longev

      Volume: 2017 Issue: 1 Pages: 1-14

    • DOI

      10.1155/2017/3759153

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Establishment of high hypoxanthine phosphoribosyltransferase activity-uricase knockout mice as novel hyperuricemic model and effects of purine/nonpurine type xanthine oxidoreductase inhibitors2019

    • Author(s)
      Takuji Hosoya, Syunya Uchida, Shigeru Shibata, Naoko H. Tomioka, Makoto Hosoyamada
    • Organizer
      18th Symposium on Purine and Pyrimidine Metabolism in Man (PP19)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 新規高尿酸血症モデル HPRT高活性Uox-KOマウスに対する プリン型およ及び非プリン型XOR阻害薬の尿酸代謝に与える影響2019

    • Author(s)
      細谷 拓司、内田 俊也,柴田 茂、富岡 直子、細山田 真
    • Organizer
      第52回日本痛風核酸代謝学会
    • Related Report
      2018 Research-status Report
  • [Presentation] HPRT高活性XDHノックアウトマウスの寿命延長2019

    • Author(s)
      細山田 真、渡部 多真紀、富岡 直子、渡辺 茂和、大坪 俊夫、市田 公美
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 新規高尿酸血症モデルHPRT高活性Uox-KOマウスに対するプリン型及び非プリン型キサンチン酸化還元酵素阻害薬の効果2019

    • Author(s)
      細谷 拓司、富岡 直子、細山田 真
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Hprt高活性Xorノックアウトマウスの寿命延長メカニズムの検討2018

    • Author(s)
      細山田 真、福内 友子、富岡 直子、市田 公美、金子 希代子、大坪 俊夫
    • Organizer
      第61回日本腎臓学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Life span extension of xanthine oxidoreductase knockout mouse by increase of HPRT activity2018

    • Author(s)
      Makoto Hosoyamada, Naoko H Tomioka, Tomoko Fukuuchi, Toshio Ohtsubo, Kiyoko Kaneko, Kimiyoshi Ichida
    • Organizer
      18th World Congress of basic and clinical Pharmacology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ヒポキサンチンホスホリボシルトランスフェラーゼ(Hprt)高活性キサンチンデヒドロゲナーゼ(Xdh)ノックアウトマウスの作出2018

    • Author(s)
      細山田 真、富岡 直子、大坪 俊夫、市田 公美、内田 俊也、鎌谷 直之
    • Organizer
      第51回日本痛風核酸代謝学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] キサンチンデヒドロゲナーゼノックアウトマウスが 短命である理由の検討2018

    • Author(s)
      安藤 太介, 細山田 真, 福内 友子, 藤田 恭子, 富岡 直子, 金子 希代子, 細山田 真, 市田 公美
    • Organizer
      日本薬学会138年会
    • Related Report
      2017 Research-status Report
  • [Patent(Industrial Property Rights)] ヒト尿酸代謝モデル動物2019

    • Inventor(s)
      細山田 真
    • Industrial Property Rights Holder
      帝京大学
    • Industrial Property Rights Type
      特許
    • Patent Publication Number
      2019-033708
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] ヒト尿酸代謝モデル動物2017

    • Inventor(s)
      細山田 真
    • Industrial Property Rights Holder
      細山田 真
    • Industrial Property Rights Type
      特許
    • Patent Publication Number
      2019-033708
    • Filing Date
      2017
    • Acquisition Date
      2019
    • Related Report
      2018 Research-status Report
  • [Patent(Industrial Property Rights)] ヒト尿酸代謝モデルマウス2017

    • Inventor(s)
      細山田 真
    • Industrial Property Rights Holder
      細山田 真
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-157930
    • Filing Date
      2017
    • Related Report
      2017 Research-status Report

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

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