Title of project or programme

Prion genetic modifiers in the mouse

Principal Investigators of project/programme grant
Title Forname Surname Institution Country
Dr Sarah Lloyd MRC Prion Unit UK
Address of institution of lead PI
Institution MRC Prion Unit
Street Address Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square
City London
Postcode WC1N 3BG
Country
  • United Kingdom
Source of funding information

Medical Research Council

Total sum awarded (Euro)

2310067.09

Start date of award

01-04-2005

Total duration of award in months

60

The project/programme is most relevant to
  • Prion disease
Keywords
Research abstract in English

Prion diseases are characterised by a prolonged incubation period which is determined by many elements including genetic factors. Polymorphisms within the prion protein gene (Prnp) are a major genetic influence on incubation time and susceptibility however it is becoming increasingly evident that variation at other genetic loci may also make a significant contribution. The identification of key polymorphisms, genes and pathways will increase our understanding of the underlying principles of prion biology, provide novel targets for therapeutic intervention and help identify those individuals at greatest risk of developing prion disease.

Linkage analysis performed to date in various mouse crosses has mapped several genetic loci of interest and our on-going research is aimed at refining these localisations and identifying candidate genes. The use of a heterogeneous stock of mice for genetic mapping has successfully reduced the size of several target regions to 1-2Mb so that a candidate gene approach is now feasible. Genes are evaluated by searching for polymorphisms within the mRNA, intron-exon boundaries and regulatory regions and are tested in the cross to assess their potential contribution to the observed phenotypic variation. Additional analysis may also be done by quantitative gene expression studies between mouse strains in both the unaffected and affected state.

As part of a Unit wide effort, we will test candidate genes for prion disease-related functions using an in-vitro assay whereby the gene function is impaired by RNAi knockdown and the effect on cell susceptibility and prion propagation is determined (Scrapie Cell Assay).

Where a promising candidate gene has been identified, new mouse models are being generated to test in-vivo whether over-expression or knockout of the gene significantly modifies prion disease incubation time as predicted by our genetic analyses.

While mouse models are an invaluable tool, our ultimate aim is to identify the genes and their polymorphisms that also influence susceptibility to various human prion diseases. To this end, quantitative trait genes successfully identified by our mouse studies are being evaluated by haplotype or single polymorphism association studies in our collections of DNA from patients affected by prion disease. In addition, these studies principally aim to understand fundamental processes, and potentially identify new therapeutic targets, which may be of generic importance in neurodegeneration and protein misfolding diseases.

Lay Summary

    Principal Investigators

    Dr S E Lloyd

    Institution

    MRC Prion Unit

    Contact information of lead PI

    Country

    United Kingdom

    Title of project or programme

    Prion genetic modifiers in the mouse

    Source of funding information

    MRC

    Total sum awarded (Euro)

    € 4,755,722

    Start date of award

    01/04/2011

    Total duration of award in years

    5.0

    The project/programme is most relevant to:

    Prion disease

    Keywords

    Research Abstract

    Prion diseases are characterised by a prolonged incubation period which is determined by many elements including genetic factors. polymorphisms within the prion protein gene (Prnp) are a major genetic influence on incubation time and susceptibility however it is becoming increasingly evident that variation at other genetic loci may also make a significant contribution. The identification of key polymorphisms, genes and pathways will increase our understanding of the underlying principles of prion Biology, provide novel targets for therapeutic intervention and help identify those individuals at greatest risk of developing prion disease.||Linkage analysis performed to date in various mouse crosses has mapped several genetic loci of interest and our on-going research is aimed at refining these localisations and identifying candidate genes. The use of a heterogeneous stock of mice for genetic mapping has successfully reduced the size of several target regions to 1-2Mb so that a candidate gene approach is now feasible. Genes are evaluated by searching for polymorphisms within the mRNA, intron-exon boundaries and regulatory regions and are tested in the cross to assess their potential contribution to the observed phenotypic variation. Additional analysis may also be done by quantitative gene expression studies between mouse strains in both the unaffected and affected state.||As part of a Unit wide effort, we will test candidate genes for prion disease-related functions using an in-vitro assay whereby the gene function is impaired by RNAi knockdown and the effect on cell susceptibility and prion propagation is determined (Scrapie Cell Assay).||Where a promising candidate gene has been identified, new mouse models are being generated to test in-vivo whether over-expression or knockout of the gene significantly modifies prion disease incubation time as predicted by our genetic analyses.||While mouse models are an invaluable tool, our ultimate aim is to identify the genes and their polymorphisms that also influence susceptibility to various human prion diseases. To this end, quantitative trait genes successfully identified by our mouse studies are being evaluated by haplotype or single polymorphism association studies in our collections of DNA from patients affected by prion disease. In addition, these studies principally aim to understand fundamental processes, and potentially identify new therapeutic targets, which may be of generic importance in neurodegeneration and protein misfolding diseases.

    Lay Summary

    Prion diseases in both humans and animals are characterised by a long, silent incubation periods before the disease emerges and this time interval varies greatly between individuals. Differences in our genetic makeup are a key factor in this variability. We already know that natural variation within one key gene, the prion protein gene, has a major influence on incubation time but it is now clear that a number of other genes are also important. If we can identify these genes and then find out what they do and how they vary between individuals we will have a much better understanding of the disease and why some individuals exposed to BSE have developed variant CJD and others have not. It may be that many others are infected but are still incubating the disease and the identification of these genes should allow much better predictions of any human epidemic. Such information should also cast light on the fundamental processes involved in these diseases and may provide new targets for drug therapies.||Identifying such genes in humans is extremely challenging and we have chosen to start our search in laboratory mice. Genetic studies of large mouse families have enabled us to narrow our search from the many thousands of genes down to a few hundred. We then look in detail at the DNA sequence of these candidate genes to find the small number of genes of importance. To show we have found the correct genes we will evaluate them in a cell based system to see if the gene influences cell susceptibility and prion replication. The ultimate proof that we have the right gene is provided by modifying the gene in mice and seeing if that actually results in the expected change in incubation period. Mice have largely the same genes as humans and so if we can find the key genes in mice, we can readily find their human counterparts. To test whether a candidate gene identified in our mouse studies is also important in human prion diseases we will search for variation in the equivalent human gene and use statistical analysis to test whether there is a link between genetic difference and susceptibility to human prion diseases such as variant CJD. Prion diseases share many features with other diseases of the ageing brain therefore the genes identified in these studies are expected to identify pathways and new therapeutic targets that are of wider relevance in neurodegeneration.

    Further information available at:

Types: Investments > €500k
Member States: United Kingdom
Diseases: Prion disease
Years: 2011
Database Categories: N/A
Database Tags: N/A

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