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Transcription profiling of mouse wild type, Fah and Fah, p21 ON and OFF NTBC animals

ABSTRACT: Fumarylacetoacetate hydrolase (Fah), the last enzyme of the tyrosine degradation pathway, is specifically expressed in hepatocytes in the liver. Loss of Fah leads to liver failure in mice within 6-8 weeks. This can be prevented by blocking tyrosine degradation upstream of Fah with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Here, we investigate the impact of p21 on global gene expression in Fah deficiency. Experiment Overall Design: Livers from adult wildtype, Fah or Fah, p21 knockout mice were analyzed either after continuous treatment (ON) with NTBC or after NTBC withdrawal for 14 days (OFF).

ORGANISM(S): Mus musculus

SUBMITTER: Holger Willenbring

PROVIDER: E-GEOD-11098 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Wildtype, Fah and Fah, p21 ON and OFF NTBC

Project description:Fumarylacetoacetate hydrolase (Fah), the last enzyme of the tyrosine degradation pathway, is specifically expressed in hepatocytes in the liver. Loss of Fah leads to liver failure in mice within 6-8 weeks. This can be prevented by blocking tyrosine degradation upstream of Fah with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Here, we investigate the impact of p21 on global gene expression in Fah deficiency. Keywords: treatment, genotype

2008-04-09 | GSE11098 | GEO

In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions

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Human hepatocyte metaplasia in injured humanized mouse livers

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2014-09-01 | E-GEOD-58679 | biostudies-arrayexpress

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Project description:The use of patient-derived induced pluripotent stem (iPS) cells as treatment for genetic diseases entails genetic repair or transfer of genetic information as a prerequisite. We have chosen the murine model of tyrosinemia type 1 (fumarylacetoacetate hydrolase deficiency; FAH(-/-) mice) as a paradigm for hereditary metabolic liver disorders and evaluated fibroblast-derived FAH(-/-)-iPS cell lines as targets for gene correction. By aggregating FAH(-/-)-iPS cells with tetraploid embryos, we obtained FAH-/--iPS cell–derived mice, which exhibited the phenotype of the founding FAH(-/-)-mice. We then rescued the diseased phenotype by lentiviral transduction of FAH-cDNA and performed embryo aggregation with these gene-corrected FAHgc-iPS cells to obtain viable healthy mice. Our results demonstrate that iPS cell technology is a valid approach to establish mouse disease models directly from somatic cells bearing genetic defects. Furthermore, established iPS cell lines can be genetically manipulated without loss of pluripotency for treatment of genetic diseases.

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Aneuploidy as a mechanism for stress-induced liver adaptation

Project description:Over half of the mature hepatocytes in mice and humans are aneuploid and yet retain full ability to undergo mitosis. This observation has raised the question whether this unusual somatic genetic variation evolved as an adaptive mechanism to hepatic injury. According to this model, hepatotoxic insults would select for hepatocytes with specific numerical chromosome abnormalities, rendering them differentially resistant to the injury. To test this hypothesis, we utilized a strain of mice heterozygous for a mutation in homogentisic acid dioxygenase (Hgd), located on chromosome 16. Loss of this allele can protect from fumarylacetoacetate hydrolase (Fah) deficiency. When adult Hgd+/- Fah-/- mice were exposed to chronic liver damage, injury-resistant nodules consisting of Hgd-null hepatocytes rapidly emerged. To determine whether aneuploidy played a role in this phenomenon, array comparative genomic hybridization (aCGH) and metaphase karyotyping were performed. Strikingly, loss of chromosome 16 was dramatically enriched in all mice that became completely resistant to tyrosinemia-induced hepatic injury. The frequency of chromosome 16-specific aneuploidy was ~50%. This result provides proof-of-principle that the selection of a specific aneuploid karyotype can result in the adaptation of hepatocytes to chronic liver injury. The extent to which aneuploidy promotes hepatic adaptation in humans is under investigation. 8 mouse hepatocyte samples were analyzed. Genomic DNA samples were derived from wild type mice (2), Hgd-/- Fah-/- mice off NTBC (2) and Hgd+/- Fah-/- off NTBC (4). Samples were compared to sex-mismatched reference genomic DNA isolated from wild type mouse splenocytes.

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