The aims of this program are:
- To create models which accurately reflect important human liver diseases;
- To identify genes which confer susceptibility to these diseases and determine severity or progression to fibrosis and cirrhosis;
- To facilitate further investigation of disease pathogenesis;
- To evaluate potential therapeutic interventions both in phenotypically faithful models and by translational clinical trails.
In collaboration with Professors S. Brown and R. Cox we have already used phenotype driven ENU mutagenesis screens to generate novel models of Non-Alcoholic Fatty Liver Disease (NAFLD/NASH) on a background of insulin resistance and have generated a model of genetically induced alcohol addiction (with Dr S. Knapp). These models are the subject of ongoing study. In order to improve our understanding of a broad range of liver diseases we will develop new models using ENU mutagenesis. Identification of the genes responsible may show us which biological pathways are important and where treatments might be targeted. To this end we are taking the following approaches:
Phenotypically screening mice from an ENU mutagenesis program for:
- Non-Alcoholic Fatty Liver Disease (NAFLD/NASH) and its associated features of diabetes, dyslipidaemia and obesity.
- Genetic sensitivity to drug induced liver injury (DILI) or toxicity induced by commonly used agents including Paracetamol (Acetaminophen), Isoniazid & Amoxicillin/Clavulanate (Augmentin).
- Genetic sensitivity to primary biliary cirrhosis (PBC) induced by pyruvate dehydrogenase complex exposure.
- Identification of mutations in candidate genes identified in human association studies.
- Further study of new and existing models of liver disease to increase understanding of disease pathogenesis and to explore novel therapeutic options.
Group Members & Collaborators
This program represents a multicenter collaborative research effort led by Professor Howard Thomas at Imperial College London. Other senior members of our group include:
- Newcastle University Dr Q.M. Anstee
- Imperial College London Professor M. Thursz & Dr R. Goldin
- MRC Mammalian Genetics Unit Professors S. Brown & R. Cox
Our collaborators include leading academic hepatologists and scientists from institutions throughout the United Kingdom:
- Newcastle University Professors A. Burt, C. Day, A. Daly & D. Jones
- Edinburgh University Professors J. Iredale & S. Forbes
- Liverpool University Professor K. Park