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Generation of humanized rats expressing drug-metabolizing enzyme using human artificial chromosome and genome editing technologies

Research Project

Project/Area Number 15H04285
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Laboratory animal science
Research InstitutionTottori University

Principal Investigator

KAZUKI Yasuhiro  鳥取大学, 医学(系)研究科(研究院), 准教授 (90403401)

Co-Investigator(Kenkyū-buntansha) 平林 真澄  生理学研究所, 行動・代謝分子解析センター, 准教授 (20353435)
Project Period (FY) 2015-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2016: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2015: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Keywordsリサーチバイオリソース / ヒト化モデル動物
Outline of Final Research Achievements

Humanized animals, in which drug metabolism-related genes of experimental animals are replaced into those of humans, are considered to play a major role in predicting human-specific drug metabolism and safety. In this study, we aimed to generate humanized animals using rats that can collect blood over time and have abundant background data such as toxicity tests among experimental animals. Specifically, following studies were performed. 1) CYP3A gene cluster and UGT2 gene cluster, which are related in human-specific drug metabolism, were introduced into rats using mouse artificial chromosome technology. 2) The rat gene cluster corresponding to the above human cluster was desrupted using the genome editing technique. 3) By mating 1) and 2), a fully humanized model rats showing human-specific metabolic ability were successfully generated.

Academic Significance and Societal Importance of the Research Achievements

本研究で開発したヒト薬物代謝関連遺伝子をヒト化したモデルラットはこれまでに開発されたヒト化マウスの特徴と、マウスにはないラットの特徴(経時採血が容易、背景データが豊富など)の両方の特徴を兼ね備えており、これまでのヒト化マウスよりも、ヒトの薬物代謝や毒性を予測するために有用なモデルになると考えられる。また、本研究開発によって、ヒトに対する安全性予測が向上すると共に、医薬品開発のスピードアップと成功確率が向上し、新薬開発の低コスト化、ひいては国民医療負担を減らすことにつながるインパクトを与え、ライフ・イノベーションの推進に大きく貢献できるものと考える。

Report

(6 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (28 results)

All 2020 2019 2018 2017 2016 2015 Other

All Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 11 results,  Open Access: 9 results,  Acknowledgement Compliant: 1 results) Presentation (13 results) (of which Invited: 9 results) Book (1 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Transchromosomic technology for genomically humanized animals2020

    • Author(s)
      Moriwaki Takashi、Abe Satoshi、Oshimura Mitsuo、Kazuki Yasuhiro
    • Journal Title

      Experimental Cell Research

      Volume: 390 Issue: 2 Pages: 111914-111914

    • DOI

      10.1016/j.yexcr.2020.111914

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Humanized UGT2 and CYP3A transchromosomic rats for improved prediction of human drug metabolism2019

    • Author(s)
      Kazuki Yasuhiro、Kobayashi Kaoru、他23名
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 116 Issue: 8 Pages: 3072-3081

    • DOI

      10.1073/pnas.1808255116

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Human and mouse artificial chromosome technologies for studies of pharmacokinetics and toxicokinetics2018

    • Author(s)
      Satoh Daisuke、Abe Satoshi、Kobayashi Kaoru、Nakajima Yoshihiro、Oshimura Mitsuo、Kazuki Yasuhiro
    • Journal Title

      Drug Metabolism and Pharmacokinetics

      Volume: 33 Issue: 1 Pages: 17-30

    • DOI

      10.1016/j.dmpk.2018.01.002

    • NAID

      210000187371

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Combinations of chromosome transfer and genome editing for the development of cell/animal models of human disease and humanized animal models2017

    • Author(s)
      Uno Narumi、Abe Satoshi、Oshimura Mitsuo、Kazuki Yasuhiro
    • Journal Title

      Journal of Human Genetics

      Volume: 63 Issue: 2 Pages: 145-156

    • DOI

      10.1038/s10038-017-0378-7

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The effect of supplementation of amino acids and taurine to modified KSOM culture medium on rat embryo development.2016

    • Author(s)
      Nakamura K, Morimoto K, Shima K, Yoshimura Y, Kazuki Y, Suzuki O, Matsuda J, Ohbayashi T.
    • Journal Title

      Theriogenology

      Volume: 86 Issue: 8 Pages: 2083-2090

    • DOI

      10.1016/j.theriogenology.2016.07.001

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Highly Efficient Transfer of Chromosomes to a Broad Range of Target Cells Using Chinese Hamster Ovary Cells Expressing Murine Leukemia Virus-Derived Envelope Proteins.2016

    • Author(s)
      Suzuki T, Kazuki Y, Oshimura M, Hara T.
    • Journal Title

      PLoS One.

      Volume: 11 Issue: 6 Pages: e0157187-e0157187

    • DOI

      10.1371/journal.pone.0157187

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cyp3a deficiency enhances androgen receptor activity and cholesterol synthesis in the mouse prostate.2016

    • Author(s)
      Hashimoto M, Kobayashi K, Yamazaki M, Kazuki Y, Takehara S, Oshimura M, Chiba K. Cyp3a deficiency enhances androgen receptor activity and cholesterol synthesis in the mouse prostate.
    • Journal Title

      J Steroid Biochem Mol Biol.

      Volume: 163 Pages: 121-128

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Thalidomide-induced limb abnormalities in a humanized CYP3A mouse model.2016

    • Author(s)
      Kazuki Y, Akita M, Kobayashi K, Osaki M, Satoh D, Ohta R, Abe S, Takehara S, Kazuki K, Yamazaki H, Kamataki T, Oshimura M.
    • Journal Title

      Sci Rep.

      Volume: 6 Issue: 1 Pages: 21419-21419

    • DOI

      10.1038/srep21419

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a High-Sensitivity Quantitation Method for Arginine Vasopressin by High-Performance Liquid Chromatography Tandem Mass Spectrometry, and Comparison with Quantitative Values by Radioimmunoassay2016

    • Author(s)
      Tsukazaki Y, Senda N, Kubo K, Yamada S, Kugoh H, Kazuki Y, Oshimura M.
    • Journal Title

      Analytical Sciences

      Volume: 32 Issue: 2 Pages: 153-159

    • DOI

      10.2116/analsci.32.153

    • NAID

      130005125625

    • ISSN
      0910-6340, 1348-2246
    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Murine Cyp3a knockout chimeric mice with humanized liver: prediction of the metabolic profile of nefazodone in humans.2016

    • Author(s)
      Nakada N, Kawamura A, Kamimura H, Sato K, Kazuki Y, Kakuni M, Ohbuchi M, Kato K, Tateno C, Oshimura M, Usui T.
    • Journal Title

      Biopharm Drug Dispos.

      Volume: 37 Issue: 1 Pages: 3-14

    • DOI

      10.1002/bdd.1990

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of Murine Cyp3a Knockout Chimeric Mice with Humanized Liver.2015

    • Author(s)
      Kato K, Ohbuchi M, Hamamura S, Ohshita H, Kazuki Y, Oshimura M, Sato K, Nakada N, Kawamura A, Usui T, Kamimura H, Tateno C.
    • Journal Title

      Drug Metab Dispos.

      Volume: 43 Issue: 8 Pages: 1208-1217

    • DOI

      10.1124/dmd.115.063479

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 染色体工学技術の創薬研究への応用2020

    • Author(s)
      香月康宏
    • Organizer
      東京大学 薬学部大学院セミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ヒト/マウス人工染色体技術応用(14):ヒト薬物代謝予測のためのヒト化UGT2およびCYP3Aトランスクロモソミックラットの作製2019

    • Author(s)
      阿部智志
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 人工染色体技術を用いた創薬研究への応用2019

    • Author(s)
      香月康宏
    • Organizer
      第20回日本毒性病理学会・教育セミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 人工染色体技術を用いた創薬研究への応用2019

    • Author(s)
      香月康宏
    • Organizer
      第46回日本毒性学会学術年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ヒト/マウス人工染色体を用いたゲノムライティングと応用2019

    • Author(s)
      香月康宏
    • Organizer
      第8回ExCELLSセミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 人工染色体技術によるデザイン染色体の構築2019

    • Author(s)
      香月康宏
    • Organizer
      「デザイン細胞医薬」ワークショップ
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 人工染色体技術を用いた創薬研究への応用2019

    • Author(s)
      香月康宏
    • Organizer
      第1回医薬品毒性機序研究会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 人工染色体技術を用いた創薬研究への応用2019

    • Author(s)
      香月康宏
    • Organizer
      平成30年度HTS バイオ分子設計研究会講演会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 最先端染色体工学技術の創薬研究への応用2018

    • Author(s)
      香月康宏
    • Organizer
      平成30年度 内外環境・代謝酵素研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 最先端染色体工学技術の創薬研究への応用2017

    • Author(s)
      香月康宏
    • Organizer
      薬物動態談話会第40年回
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] ヒト薬物代謝予測のためのマウス人工染色体とゲノム編集によるヒト化CYP3Aラットの作製2016

    • Author(s)
      香月康宏
    • Organizer
      日本薬物動態学会第31回年会
    • Place of Presentation
      キッセイ文化ホール/松本市総合体育館(長野県松本市)
    • Year and Date
      2016-10-13
    • Related Report
      2016 Annual Research Report
  • [Presentation] 染色体工学技術によるヒト化動物の作製と医学・薬学応用2016

    • Author(s)
      香月康宏
    • Organizer
      第23回HAB研究機構学術年会
    • Place of Presentation
      つくば産業技術総合研究所(茨城県つくば市)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 染色体工学技術を用いた新規トランスクロモソミック動物作製システムの開発2015

    • Author(s)
      香月康宏
    • Organizer
      日本実験動物学会
    • Place of Presentation
      京都テルサ(京都府京都市)
    • Year and Date
      2015-05-29
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Book] 進化するゲノム編集技術、真下知士 城石俊彦 監修2015

    • Author(s)
      香月康宏、押村光雄
    • Total Pages
      341
    • Publisher
      (株)NTS
    • Related Report
      2015 Annual Research Report
  • [Remarks] 日本薬物動態学会第31回年会(松本)ベストポスター賞受賞

    • URL

      http://www.med.tottori-u.ac.jp/chromosome/535/20495.html

    • Related Report
      2016 Annual Research Report
  • [Remarks] 第62回日本実験動物学会総会 (第27回)奨励賞受賞

    • URL

      http://www.med.tottori-u.ac.jp/chromosome/535/nihonjikkendoubutu.html

    • Related Report
      2015 Annual Research Report
  • [Patent(Industrial Property Rights)] ヒトの薬物代謝酵素誘導及び薬物動態予測が可能な新規薬物代謝酵素誘導評価方法2016

    • Inventor(s)
      香月康宏、阿部智志、押村光雄
    • Industrial Property Rights Holder
      鳥取大学、Trans Chromosomics
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2016-200468
    • Filing Date
      2016-10-11
    • Related Report
      2016 Annual Research Report

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Published: 2015-04-16   Modified: 2022-11-04  

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