A GENETIC APPROACH TO DEVELOP NOVEL MOUSE MODELS OF LIVER DISEASE

Liver disease is now the 5th most common cause of death in the United Kingdom and about 4% of the population have evidence of ongoing liver damage. It is important to find out more about the causes of liver disease so that new treatments can be developed or to prevent liver damage occurring. This project aims to help us unravel some of the complex biology behind liver disease so that we can develop and evaluate new treatments in the future. It is clear that many factors contribute to the development of liver disease in patients and one of those factors is their genetic background. We will identify contributory genes by taking mice with random mutations in their DNA and screening for liver abnormalities. As liver disease may occur when a susceptible person is challenged with a drug, alcohol or by being overweight we will use the challenges to increase the sensitivity of our screening programme. Therefore, in addition to identifying the most important genes which cause liver disease we will also develop mouse models of liver disease which could be used for testing new treatments.

The majority of common liver diseases are complex traits where multiple genes interact with environmental factors to determine the disease phenotype. A small number of host genetic factors which determine the susceptibility to specific liver diseases and to liver fibrosis have been identified but the majority remain to be discovered.
Animal models for a variety of liver diseases have been described in the literature. Frequently, these do not faithfully replicate the human disease. Such discrepancies reduce the usefulness of these models and may lead one to question whether observations made using these models are truly applicable in man.
N-ethyl-N-nitrosurea (ENU) mutagenesis allows the identification of novel phenotypes that, in addition to aiding pathogenic gene identification, may more accurately reflect the subtleties of the human diseases they model. Previous studies by collaborators in this project have used this technique to generate a line of mice, with a mutation in the a1 subunit of the GABAA receptor, which imbibe large quantities of alcohol and allele association studies now indicate involvement of the same and related genes in human alcoholism. A second study has established a new model of NAFLD that may better replicate the human disease phenotype than any existing model.
We now wish to build on this initial experience to identify further genes involved in the pathogenesis of alcohol-related steatohepatitis (ASH) and non-alcoholic steatohepatitis (NAFLD), two of the most common chronic liver diseases, and drug induced and autoimmune liver diseases.