Laboratory Animal Research Department

Biomedical Research Laboratory

Biomedical Research Laboratory has been creating a new humanized animal model by modification of NOG mice, especially focusing on development of a liver-humanized model. We established TK-NOG strain which is a drug-induced liver failure model. The expression unit of herpes simplex virus thymidine kinase was introduced to NOG mouse by using microinjection technique. The TK-NOG mice can bear human hepatocytes at high rates on the basis of extremely high acceptability of xenogeneic cells. We succeeded to replace the mouse liver nearly 80% with human hepatocytes. The "humanized liver" reconstructed with human hepatocytes has been shown to have drug metabolizing properties similar to those of the human liver. In addition, we further improve the NOG mouse by using a microsatellite marker assisted selection protocol (known as speed congenic) to efficiently replace the genetic background of conventional transgenic mouse and knockout mouse to that of NOG strain (super immunnodeficient) while preserving the characteristics.

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※Reference
  1. Baseline quasispecies selection and novel mutations contribute to emerging resistance-associated substitutions in hepatitis C virus after direct-acting antiviral treatment.
    Kai Y, Hikita H, Morishita N, Murai K, Nakabori T, Iio S, Hagiwara H, Imai Y, Tamura S, Tsutsui S, Naito M, Nishiuchi M, Kondo Y, Kato T, Suemizu H, Yamada R, Oze T, Yakushijin T, Hiramatsu N, Sakamori R, Tatsumi T, Takehara T.
    Sci Rep. 2017 Jan 30;7:41660
  2. Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice.
    Shimizu M, Suemizu H, Mitsui M, Shibata N, Guengerich FP, Yamazaki H.
    Xenobiotica 2016 Nov 16:1-5.
  3. Study on AAV-mediated gene therapy for diabetes in humanized liver mouse to predict efficacy in humans.
    Hashimoto H, Mizushima T, Ogura T, Kagawa T, Tomiyama K, Takahashi R, Yagoto M, Kawai K, Chijiwa T, Nakamura M, Suemizu H.
    Biochem Biophys Res Commun. 2016 Sep 23;478(3):1254-60.
  4. Simulation of human plasma concentration-time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite using humanized chimeric mice and semi-physiological pharmacokinetic modeling.
    Kamimura H, Ito S, Chijiwa H, Okuzono T, Ishiguro T, Yamamoto Y, Nishinoaki S, Ninomiya SI, Mitsui M, Kalgutkar AS, Yamazaki H, Suemizu H.
    Xenobiotica. 2016 Jul 7:1-12.
  5. Combining Chimeric Mice with Humanized Liver, Mass Spectrometry, and Physiologically-Based Pharmacokinetic Modeling in Toxicology.
    Yamazaki H, Suemizu H, Mitsui M, Shimizu M, Guengerich FP.
    Chem Res Toxicol. 2016 Jul 5.
  6. Sodium taurocholate cotransporting polypeptide inhibition efficiently blocks hepatitis B virus spread in mice with a humanized liver.
    Nakabori T, Hikita H, Murai K, Nozaki Y, Kai Y, Makino Y, Saito Y, Tanaka S, Wada H, Eguchi H, Takahashi T, Suemizu H, Sakamori R, Hiramatsu N, Tatsumi T, Takehara T.
    Sci Rep. 2016 Jun 9;6:27782.
  7. Sodium taurocholate cotransporting polypeptide inhibition efficiently blocks hepatitis B virus spread in mice with a humanized liver.
    Nakabori T, Hikita H, Murai K, Nozaki Y, Kai Y, Makino Y, Saito Y, Tanaka S, Wada H, Eguchi H, Takahashi T, Suemizu H, Sakamori R, Hiramatsu N, Tatsumi T, Takehara T.
    Sci Rep. 2016 Jun 9;6:27782.
  8. The human hepatic cell line HepaRG as a possible cell source for the generation of humanized liver TK-NOG mice.
    Higuchi Y, Kawai K, Yamazaki H, Nakamura M, Bree F, Guguen-Guillouzo C, Suemizu H.
    Xenobiotica. 2014 Jan;44(2):146-53.

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