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Title: Genomic evaluation of models of human disease : the Fechm1pas model of Erythropoietic Protoporphyria
Authors: Barker, Colin
Award date: 2006
Presented at: University of Leicester
Abstract: Erythropoeitic protoporphyria (EPP) is a member of the prophyria disease class and is caused by abnormal function of the enzyme ferrochelatase (Fech). In humans it has variable penetrance, but primarily leads to toxicity in the skin and liver to varying degrees. Here I have investigated the nature of EPP progression using the Fechm1PAS mouse model. This mouse contains a point mutation in the fech gene which results in reduced Fech activity to <7% of wild type, with resultant loss of haem, anaemia and hepatic cholestasis. The phenotypic progression of Fechm1PAS/m1PAS mice was established using pathology and clinical biochemistry from 18 days gestation to 32 weeks of age. Pathological changes were found from 4 weeks with biochemical and differential gene expression (DGE) analysis showing intraheptic cholestasis from birth. Genomic data from cDNA microarrays was derived and analysed with the DGE by phenotypic anchoring. DGE was observed in all processes responsible for cell protection and epigenetic regulation. DGE analysis have led me to hypothesise that the porphyria leads to a chronic reactive oxygen species (ROS) attack, causing DNA damage, eventually leading to hepatocarinoma. This was indicated by changes in the GSH, cytochrome P450, circadian rhythm and methylation pathways. DGE in these processes included downregulation of DNA methyltransferases (Dnmt1, Dnmt6a and Dnmt6b), and upregulation of cytochrome oxidase (Cox and Por) and GSH metabolism transcription factors (Gclc and Gclm). The findings made here contribute further to the understanding of EPP progression and the relationship between phenotype and DGE in EPP.
Type: Thesis
Level: Doctoral
Qualification: PhD
Rights: Copyright © the author. All rights reserved.
Appears in Collections:Theses, MRC Toxicology Unit
Leicester Theses

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