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.

Publications

10 25 50
 
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 Academic/University
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