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CJD and BSE: an integrated molecular and experimental neuropathological analysis of prion neurodegeneration, strain variation and transmission risks

Objective

We will study the transmission characteristics of new variant CJD and its possible relationship with BSE, and further study the molecular basis of prion stain diversity with a particular emphasis on Prion Protein (PrP) glycosylation.
In addition, the cellular pathogenesis of prion diseases and the interactions between bovine and human PrP will be examined and we aim to identify mutant prion proteins which may induce spontaneous spongiform neurodegeneration.
We plan to generate BSE specific antibodies to develop specific assays for BSE diagnosis.

Prion diseases are transmissible neurodegenerative diseases of humans and animals; the transmissible agent or prion appears to consist principally of a modified form of a host encoded protein. They represent an increasingly important research area because of both their unique biology and the recent occurrence of an epidemic animal prion disease, bovine spongiform encephalopathy (BSE), which has led to fears of transmission to humans through dietary or occupational exposure. The recent occurrence of a new recognised clinicopathological variant of CJD affecting young people in the UK and now France has led to considerable alarm that these cases represent BSE transmission. Such concerns have had a major impact on the EU agricultural industry, cases of BSE are now being reported throughout the EU. In addition, there have been concerns over the safety of pharmaceutical products derived from human or bovine tissues. Most of the participants in this application are partners in an existing. EC Shared cost action on prion diseases and the current application aims to complement and strengthen this partnership to respond to the challenges posed by BSE. We will attempt to determine whether these new cases are related to BSE by comparative transmission studies in transgenic mice with increased susceptibility to human prions.

We will develop and evaluate a range of transgenic mouse, cell culture and in vitro models to further allow experimental estimation of the risks of transmission of BSE to humans and which should also provide the tools to study the molecular mechanisms of prion propagation and the causes of prion neurodegeneration. The molecular basis of strain variation in prion diseases remains to be established and a number of molecular approaches will be attempted to study this. This application links directly with both current EC Concerted Actions in this area, which, in addition to providing tissues for study, allows all the activities in this proposal to be placed in a neuropathlogical and epidemiological context within the EU. The prion diseases are now the best understood neurodegenerative conditions and advances made in this area are already providing insights into processes of neurodegeneration, which may well, be of much wider application. The recent identification of prion-like mechanisms in yeast suggests that the novel biology involved may not be restricted to this group of diseases but be of wider pathobiological importance. 04

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
Address
Norfolk Place Imperial College School Of Medicine
W2 1PG London
United Kingdom

Participants (8)

ARISTOTLE UNIVERSITY OF THESSALONIKI
Greece
Address

54006 Thessaloniki
Bundesforschungsanstalt für Viruskrankheiten der Tiere
Germany
Address
Paul-ehrlich-straße
72076 Tübingen
DEUTSCHES PRIMATENZENTRUM GMBH
Germany
Address
4,Kellnerweg 4
37077 Göttingen
Georg-August-Universität Göttingen
Germany
Address
40,Robert-koch-strasse
37075 Göttingen
Institute of Psychiatry
United Kingdom
Address
De Crespigny Park
SE5 8AF London
Universität Wien
Austria
Address
18-20,Währinger Gürtel
1097 Wien
Universität Zürich
Switzerland
Address
12,Schmelzbergstrasse
8091 Zürich
Western General Hospital
United Kingdom
Address
Crewe Road
EH4 2XU Edinburgh