Principal Investigators


Dr E A Asante

Institution


MRC Prion Unit

Contact information of lead PI


Country


United Kingdom

Title of project or programme


Transgenic modelling of human prion diseases, intermammalian transmission barriers & assessing candidate therapeutics

Source of funding information


MRC

Total sum awarded (Euro)


€ 8,813,360

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


In studies now spanning well over a decade we have developed highly specialised transgenic transmission facilities for comprehensive studies of human prion disease under appropriate biocontainment. Species-barrier-free transmission of many forms of human prion disease is available. While excellent, well characterised models are now in routine use, further improvement to these models, and the development of improved models for the assay of vCJD prions are underway. In addition to ongoing basic research into intermammalian and strain-specific transmission barriers and characterisation of the prion strains causing human disease, this facility is being applied to address key public health issues which require human prion bioassay (tissue distribution of infectivity and human prion decontamination for example) and to study putative prion therapeutics. Animal models of a range of inherited human prion diseases are being studied, in particular to determine if prions are produced spontaneously in such animals. The specific aims of this programme are as follows:- To establish the full range of prion strains causing human disease and to attempt to biologically clone these for biochemical study (with programme 6) – To complete our long-term characterisation of intermammalian prion transmission barriers of relevance to public health and to understand the interaction between prion strain diversity and these barriers – To model the human inherited prion diseases and determine whether prions can be generated spontaneously in these models – To generate new transgenic lines as required to model novel human PrP polymorphisms and candidate prion modifier genes (in conjunction with programmes 1 and 2) – To generate transgenic models of frontotemporal dementia (in conjunction with programme 10) – Development and use of standardised models for evaluation of candidate therapeutics – To continue to provide and update the Units Transgenic Core facility and support animal research throughout the Unit

Lay Summary


While the Unit is working to find alternatives to the use of laboratory animals in our research, at this time some crucial work can only be done in mice. We have developed a key series of animal models of human prion disease. This involves introducing various forms of the human prion protein gene into mice so that they produce human protein. This includes both the M and the V form, as well as various genetic mutations that are seen in patients with inherited forms of prion disease (also known as familial CJD and GSS). Such mice are very sensitive to infection with CJD prions and have allowed us to study the various strains of human prions, including notably the strain which causes variant CJD. These studies have formed an important part of the evidence showing that variant CJD is the human counterpart of BSE and we have been able to reproduce the characteristic features of variant CJD seen down the microscope (known as florid plaques) in these mice. This model then allows us to test possible treatments for the human disease. Another key area of this research is to understand the so-called species barrier that limits the ability of prions from one species of animal to infect another. The most important of these barriers for us to study is that between cows and humans, but obviously we cannot study this directly by infecting humans so instead we use these special mice (known as transgenic mice) in which we have placed a human prion protein gene in order to estimate how large this barrier may be and to begin to understand how the barrier works. We are also studying some of the inherited prion diseases using mice. by putting the mutant human gene in mice, we can study how it causes disease in those families with a faulty prion protein gene.

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