We have developed a novel method for producing chimeric mice with fully mature and functional human liver tissue, which is maintained in the absence of any ongoing liver pathology and without continued drug treatment. This model system overcomes the substantial problems (kidney and liver pathology, short lifespan, incomplete liver replacement) that have significantly limited the utility of existing models. To do this, a highly immunocompromised (NOG) mouse was genetically engineered to express a thymidine kinase transgene in the liver, which enabled the temporally controlled and tissue-specific ablation of mouse liver tissue after administration of a non-toxic drug (gancyclovir). After injection of human liver cells, the recipient mice were shown to have a high level of human liver reconstitution in situ, which survived for a more prolonged period (>8 months) than could be attained in any other model;and to have a gene expression profile and 3-dimensional architecture characteristic of mature human liver. First, this platform will be used to develop novel transplantation methods that enable human liver stem cells, human induced pluripotent epithelial cells (hiPS), or human adipocyte-derived stem cells to reconstitute a human liver. If successful, this would enable a complete paradigm-shift for treatment of end-stage liver disease: 'liver transplantation'could be performed using autologous cells without immunosuppression. Secondly, by genotyping the donor human liver cells, a panel of mice with 'humanized livers'with specified alleles for phase I drug metabolizing will be produced. Then, the rate of formation of human-specific drug metabolites for at least 3 drugs, whose metabolism is dependent upon human CYP450 enzyme activity, will be analyzed. If successful, this innovative model system will enable pharmacogenetic analyses to be efficiently performed within an entirely human context in vivo with all confounding environmental variables controlled, which would overcome a significant roadblock for characterizing inter-individual variation in drug metabolism.
This project will produce chimeric mice with human livers in situ from progenitor cells. If successful, this revolutionary experimental platform will enable: 'liver transplantation'to be performed using autologous cells without immunosuppression;and will provide a revolutionary platform for human pharmacogenetic analysis, which will overcome a significant roadblock for understanding inter-individual variation in drug metabolism.
|Zheng, Ming; Zhang, Haili; Dill, David L et al. (2015) The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans. PLoS Med 12:e1001782|
|Park, Walter G; Wu, Manhong; Bowen, Raffick et al. (2013) Metabolomic-derived novel cyst fluid biomarkers for pancreatic cysts: glucose and kynurenine. Gastrointest Endosc 78:295-302.e2|
|Nishimura, Toshihiko; Nishimura, Toshiko; Hu, Yajing et al. (2013) Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction. J Pharmacol Exp Ther 344:388-96|
|Peltz, Gary (2013) Can 'humanized' mice improve drug development in the 21st century? Trends Pharmacol Sci 34:255-60|
|Wu, M; Sahbaie, P; Zheng, M et al. (2013) Opiate-induced changes in brain adenosine levels and narcotic drug responses. Neuroscience 228:235-42|
|Wu, Manhong; Xu, Yue; Fitch, William L et al. (2013) Liquid chromatography/mass spectrometry methods for measuring dipeptide abundance in non-small-cell lung cancer. Rapid Commun Mass Spectrom 27:2091-8|
|Liu, Hong-Hsing; Hu, Yajing; Zheng, Ming et al. (2012) Cd14 SNPs regulate the innate immune response. Mol Immunol 51:112-27|
|Zheng, Ming; Dill, David; Clark, J David et al. (2012) Computational genetic discoveries that could improve perioperative medicine. Curr Opin Anaesthesiol 25:428-33|
|Wu, Manhong; Zheng, Ming; Zhang, Weiruo et al. (2012) Identification of drug targets by chemogenomic and metabolomic profiling in yeast. Pharmacogenet Genomics 22:877-86|
|Zheng, Ming; Dill, David; Peltz, Gary (2012) A better prognosis for genetic association studies in mice. Trends Genet 28:62-9|
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