A GENETIC APPROACH TO DEVELOP NOVEL MOUSE MODELS OF LIVER DISEASE
Lead Research Organisation:
Imperial College London
Department Name: Dept of Medicine
Abstract
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.
Technical Summary
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.
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.
Publications

Anstee QM
(2013)
Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition.
in Nature communications
Description | Clinical Lecturer starter grant |
Amount | £30,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2009 |
End | 10/2010 |
Description | MRC Experimental Medicne grant |
Amount | £720,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2008 |
End | 05/2011 |
Title | Alco-mice |
Description | Alcohol Imbibing mice with known genetic mechanism |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2008 |
Provided To Others? | Yes |
Impact | Inclusion in MRC Addiction Clusters |
Description | MRC Addiction Cluster |
Organisation | University College London |
Department | Biosciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Development of a Genetic Model of Alcoholism by ENU Mutagenesis by Dr Q Anstee, H C Thomas, and S Brown which has subsequently been studied by the MRC Addiction Cluster working on GABA. |
Collaborator Contribution | Defining the mechanism involved ubsing brain slice experimentsInvestigation of the electrophysiological effects of the ENU induced mutation associated with the alcohol preferring phenotype.Characterisation of the alcohol preferring phenotype |
Impact | Further studies to establish the mechanism operative in this model. This is multi-disciplinary involving the MRC Neuro-pharmacology group under Prof T Smart, and groups uner Prof Dai Stephens, Prof Lambert and Dr Belelli and Prof Hugh Gurling and Dr Marsha Morgan. |
Start Year | 2008 |
Description | MRC Addiction Cluster |
Organisation | University of Dundee |
Department | Division of Neuroscience |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Development of a Genetic Model of Alcoholism by ENU Mutagenesis by Dr Q Anstee, H C Thomas, and S Brown which has subsequently been studied by the MRC Addiction Cluster working on GABA. |
Collaborator Contribution | Defining the mechanism involved ubsing brain slice experimentsInvestigation of the electrophysiological effects of the ENU induced mutation associated with the alcohol preferring phenotype.Characterisation of the alcohol preferring phenotype |
Impact | Further studies to establish the mechanism operative in this model. This is multi-disciplinary involving the MRC Neuro-pharmacology group under Prof T Smart, and groups uner Prof Dai Stephens, Prof Lambert and Dr Belelli and Prof Hugh Gurling and Dr Marsha Morgan. |
Start Year | 2008 |
Description | MRC Addiction Cluster |
Organisation | University of Sussex |
Department | School of Psychology Sussex |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Development of a Genetic Model of Alcoholism by ENU Mutagenesis by Dr Q Anstee, H C Thomas, and S Brown which has subsequently been studied by the MRC Addiction Cluster working on GABA. |
Collaborator Contribution | Defining the mechanism involved ubsing brain slice experimentsInvestigation of the electrophysiological effects of the ENU induced mutation associated with the alcohol preferring phenotype.Characterisation of the alcohol preferring phenotype |
Impact | Further studies to establish the mechanism operative in this model. This is multi-disciplinary involving the MRC Neuro-pharmacology group under Prof T Smart, and groups uner Prof Dai Stephens, Prof Lambert and Dr Belelli and Prof Hugh Gurling and Dr Marsha Morgan. |
Start Year | 2008 |
Description | BBC Horizon Programme October 2010. 'A Decade of the Human Genome' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Primary Audience | Media (as a channel to the public) |
Results and Impact | The BBC Horizon team wanted to present three areas where the data from the Human Genome Project was starting to contribute to healthcare. Our ENU Mutagenesis programme has generated a mouse model of alcoholis. A genetic association study indicates that the same gene which is mutated in the mouse model is associated with alcoholism in some patients. The mouse is being studied in the MRC Addiction Cluster run by Dai Stephens and with the help of Professor Trevor Smart, Professor Jeremy Lambert and Dr Delia Belelli. Interest from members of public and NHS |
Year(s) Of Engagement Activity | 2010 |
Description | Press release Imperial College and MRC web sites. |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Primary Audience | Public/other audiences |
Results and Impact | Press release Patient recruitment to clinical trial |
Year(s) Of Engagement Activity | 2008 |