Title of project or programme

Human molecular genetics and bioinformatics

Principal Investigators of project/programme grant
Title Forname Surname Institution Country
Dr Simon Mead MRC Prion Unit UK
Address of institution of lead PI
Institution MRC Prion
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)

5521862.50

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

“The MRC Prion Unit Human Molecular Genetics of Prion and Related Dementias Programme investigates why some people, but not others, get prion diseases such as Creutzfeldt-Jakob disease (CJD). By comparing genetic differences between people who developed CJD and healthy people we hope to identify genes that influence why particular people are more susceptible to these diseases, and use this information to better estimate public health risks and to develop new tests and treatments. We also know that the fundamental processes involved in CJD, where one of the body’s own proteins becomes misshapen and then forms large clumps of material, are very relevant to other much commoner diseases such as Alzheimer’s Disease. Evidence in support of the involvement of non- PRNP genetic factors comes in part from work with laboratory inbred mouse strains, detailed in this group’s section. A small number (~5) of quantitative trait loci (QTL) responsible for determining incubation time following intra-cerebral inoculation with prions have been mapped by the MRC Prion Unit and others using different crossing strategies and prion strains. The integration of unbiased genome-wide strategies in mouse and human prion disease will be an important in the success of both programs. Our discovery research utilises recently available genome-wide genotyping technologies. We have successfully conducted a pilot genome-wide association study with EA-Affymetrix 500K arrays (Mead et al. Lancet Neurology 2009). The necessary molecular genetic, bioinformatic, and statistical genetic expertise for genome-wide association study is either available in the Unit or through collaboration. Over the next few years we expect to develop our discovery genome-wide association research in larger patient cohorts using more advanced genotyping technologies, and focus on developing cellular and animal models to test the genes identified in our discovery research. It has become increasingly apparent that neurodegenerative diseases share fundamental mechanisms involving protein misfolding, including Alzheimer’s disease and Parkinson’s disease. It is likely that genetic modifiers of prion pathogenesis may be of broader relevance to other protein misfolding diseases, and we intend to explore these possibilities. One of the key goals of bioinfomatics in the Unit is to identity modifier genes, pathways and mechanisms controlling prion pathogenesis. The objective of this aspect of the programme is to use computational and statistical methods for the analysis and integration of these Unit based large-scale experiments (and also externally generated data sets) and their resulting data sets, which are large, inherently noisy and do not produce necessarily clear candidates.”

Lay Summary

    Principal Investigators

    Dr S Mead

    Institution

    MRC Prion Unit

    Contact information of lead PI

    Country

    United Kingdom

    Title of project or programme

    Human molecular genetics and bioinformatics

    Source of funding information

    MRC

    Total sum awarded (Euro)

    € 9,153,942

    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 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.

    Lay Summary

    Human molecular genetics|Most of the UK population has been exposed to Bovine Spongiform Encephalopathy (BSE, commonly known as mad cow disease) by eating contaminated food. The germ that causes BSE, called a prion, may infect humans, resulting in a fatal brain illness called variant Creutzfeldt-Jakob disease (vCJD). While there are few patients to date, we do not know how many might be infected with the disease and develop symptoms later. |vCJD has so far only affected one genetic subtype of individual, found in 40% of healthy people in the UK. Whether other genetic types will become affected, and if so whether they will have an illness like vCJD is unknown. It is clear that genes are important in controlling who will get vCJD. To study this we are using modern technologies to measure many hundreds of thousands of different genetic types, and compare these between groups of the healthy population and vCJD patients.|We are also developing and applying methods to extract, combine and make sense of the huge amount of genetic and other information which is generated by scientists working in the field of molecular Biology and Prion research around the world.|Bioinformatics|We are developing and applying methods to extract, combine and make sense of the huge amount of data which is generated by scientists working in the field of molecular Biology and Prion research around the world. This includes large sets of data generated by us in the Prion Unit, towards furthering our understanding of the underlying principles of Prion disease. We are able to do this through information technology and the use of fast computers, software programs for analysis and access to data via the internet.

    Further information available at:

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

Export as PDF