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実験動物応用研究部

ヒト臓器/組織モデル研究室

ヒト臓器/組織モデル研究室では、NOGマウスの改良により、新たなヒト化モデル動物の作製を行っています。特に肝臓を標的としたヒト化モデルの開発に注力しており、薬剤により肝障害を誘導する単純ヘルペスウイルスチミジンキナーゼ（HSVtk）を肝臓で発現させるユニットを、マイクロインジェクション法により遺伝子導入した改良型マウス（TK-NOG）は、NOGマウスの極めて高い異種細胞受容性を活かし、高率でヒト肝臓細胞を保有することが可能です。既にマウス肝臓の8割近くをヒト肝臓細胞で置換することに、成功しています。ヒト肝細胞で再構築された“ヒト化肝臓”はヒト肝臓と同様な薬物代謝特性を示すことが明らかとなっています。また、在来のトランスジェニックマウスやノックアウトマウスの特性を保持したまま、遺伝背景を効率よくNOG化（超免疫不全化）するための方法として、マイクロサテライトマーカー選抜によるスピードコンジェニック法を開発し、NOGマウスのさらなる改良を行っています。

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TK-NOGマウスの詳細はこちら
※代表的な研究論文
  1. Methyl-hydroxylation and subsequent oxidation to produce carboxylic acid is the major metabolic pathway of tolbutamide in chimeric TK-NOG mice transplanted with human hepatocytes.
    Uehara S, Yoneda N, Higuchi Y, Yamazaki H, Suemizu H.
    Xenobiotica. 2021 May;51(5):582-589.
  2. Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production.
    Myojin Y, Hikita H, Sugiyama M, Sasaki Y, Fukumoto K, Sakane S, Makino Y, Takemura N, Yamada R, Shigekawa M, Kodama T, Sakamori R, Kobayashi S, Tatsumi T, Suemizu H, Eguchi H, Kokudo N, Mizokami M, Takehara T.
    Gastroenterology. 2021 Apr;160(5):1741-1754.e16.
  3. Different Hepatic Concentrations of Bromobenzene, 1,2-Dibromobenzene, and 1,4-Dibromobenzene in Humanized-Liver Mice Predicted Using Simplified Physiologically Based Pharmacokinetic Models as Putative Markers of Toxicological Potential.
    Miura T, Shimizu M, Uehara S, Yoshizawa M, Nakano A, Yanagi M, Kamiya Y, Murayama N, Suemizu H, Yamazaki H.
    Chem Res Toxicol. 2020 Dec 21;33(12):3048-3053.
  4. Comparative Transcriptomics Analyses in Livers of Mice, Humans, and Humanized Mice Define Human-Specific Gene Networks.
    Jiang C, Li P, Ruan X, Ma Y, Kawai K, Suemizu H, Cao H.
    Cells. 2020 Nov 30;9(12):2566.
  5. Metabolic Profiles of Tetrabromobisphenol A in Humans Extrapolated from Humanized-Liver Mouse Data Using a Simplified Physiologically Based Pharmacokinetic Model.
    Miura T, Uehara S, Shigeta K, Yoshizawa M, Kamiya Y, Murayama N, Shimizu M, Suemizu H, Yamazaki H.
    Chem Res Toxicol. 2021 Feb 15;34(2):522-528.
  6. Identification of human long noncoding RNAs associated with nonalcoholic fatty liver disease and metabolic homeostasis.
    Ruan X, Li P, Ma Y, Jiang CF, Chen Y, Shi Y, Gupta N, Seifuddin F, Pirooznia M, Ohnishi Y, Yoneda N, Nishiwaki M, Dumbovic G, Rinn JL, Higuchi Y, Kawai K, Suemizu H, Cao H.
    J Clin Invest. 2021 Jan 4;131(1):e136336.
  7. Human Aldehyde Oxidase 1-Mediated Carbazeran Oxidation in Chimeric TK-NOG Mice Transplanted with Human Hepatocytes.
    Uehara S, Yoneda N, Higuchi Y, Yamazaki H, Suemizu H.
    Drug Metab Dispos. 2020 Jul;48(7):580-586.
  8. Hepatitis C virus infection suppresses hepatitis B virus replication via the RIG-I-like helicase pathway.
    H Murai K, Hikita H, Kai Y, Kondo Y, Fukuoka M, Fukutomi K, Doi A, Yamai T, Nakabori T, Fukuda R, Takahashi T, Miyakawa K, Suemizu H, Ryo A, Yamada R, Kodama T, Sakamori R, Tatsumi T, Takehara T.
    Sci Rep. 2020 Jan 22;10(1):941.
  9. Expansion, in vivo-ex vivo cycling, and genetic manipulation of primary human hepatocytes.
    Michailidis E, Vercauteren K, Mancio-Silva L, Andrus L, Jahan C, Ricardo-Lax I, Zou C, Kabbani M, Park P, Quirk C, Pyrgaki C, Razooky B, Verhoye L, Zoluthkin I, Lu WY, Forbes SJ, Chiriboga L, Theise ND, Herzog RW, Suemizu H, Schneider WM, Shlomai A, Meuleman P, Bhatia SN, Rice CM, de Jong YP.
    Proc Natl Acad Sci U S A. 2020 Jan 21;117(3):1678-1688.
  10. In vivo functional analysis of non-conserved human lncRNAs associated with cardiometabolic traits.
    Ruan X, Li P, Chen Y, Shi Y, Pirooznia M, Seifuddin F, Suemizu H, Ohnishi Y, Yoneda N, Nishiwaki M, Shepherdson J, Suresh A, Singh K, Ma Y, Jiang CF, Cao H.
    Nat Commun. 2020 Jan 2;11(1):45.
  11. Combinations of two drugs among NS3/4A inhibitors, NS5B inhibitors and non-selective antiviral agents are effective for hepatitis C virus with NS5A-P32 deletion in humanized-liver mice.
    Doi A, Hikita H, Kai Y, Tahata Y, Saito Y, Nakabori T, Yamada R, Kodama T, Sakamori R, Murayama A, Nitta S, Asahina Y, Suemizu H, Tatsumi T, Kato T, Takehara T.
    J Gastroenterol. 2019 May;54(5):449-458.
  12. Expression and inducibility of cytochrome P450s in human hepatocytes isolated from chimeric mice with humanised livers.
    Uehara S, Higuchi Y, Yoneda N, Yamazaki H, Suemizu H.
    Xenobiotica. 2019 Jun;49(6):678-687.
  13. Chimeric mice with humanized liver as a model for testing organophosphate and carbamate pesticide exposure.
    Suemizu H, Kawai K, Murayama N, Nakamura M, Yamazaki H.
    Pest Manag Sci. 2018 Jun;74(6):1424-1430.

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