Objective
There is a public health concern that the incidence of Creutzfeldt-Jakob disease (CJD) may increase over the next one or two decades because the new variant of Creutzfeldt-Jakob disease (nvCJD) is believed to have arisen from infection via meat products contaminated by the bovine spongiform encephalopathy (BSE) agent. Since there is no treatment for CJD, it is prudent to learn more about the pathogenesis of CJD and the other transmissible encephalopathies (TSEs) since greater knowledge will increase the chances of a successful treatment being devised; greater knowledge may also aid elimination of the animal TSEs.
Understanding pathogenic mechanisms usually requires knowledge of the normal corresponding physiological processes. The objectives of this proposal are to increase knowledge of the normal and pathogenic properties of the putative infectious agent, the prion protein.
We aim to focus on investigating our hypothesis that the prion protein is involved in signal transduction. We and others have demonstrated that prion protein appears to be involved in cell signalling and that this involves changes in intracellular calcium concentrations, but the particular signal transduction pathways have yet to be identified. There is also evidence that in the TSEs, disruption of normal prion protein function occurs and that this may be the mechanism underlying pathogenesis; disruption of normal prion protein function may be the mechanism whereby prion amyloid deposits exert their neurotoxic effects, since there is an absolute requirement for expression of normal prion protein for the pathogenic forms of the prion protein to exert their neurotoxicity.
Understanding prion protein function will therefore most probably help us to understand the neurodegenerative mechanisms in the TSEs and lead to the identification of therapeutic targets for CJD. The proposed consortium will bring together complementary scientific expertise in TSE pathogenesis and pathology, transgenic animals, gene delivery to neurons, cell and molecular biology, intracellular calcium imaging, signal transduction, pathogenic mechanisms associated with amyloid in Alzheimer's disease, and state of the art protein chemistry and protein sequencing; the consortium will also recruit to TSE research new scientists without prior experience of the TSE field and so expand and enhance the EU effort into treating and eliminating these important diseases.
Our specific objectives are:
- to generate stably transfected mouse neuroblastoma cell lines expressing mutant mouse prion proteins corresponding
- to known human prion mutations; - to generate similar cellular models of mutant prion protein expression, using adenoviral vectors, in primary cultures of hippocampal neurons from prion-null transgenic mice;
- to determine if the mutant prion proteins in the cell lines and in primary neuronal cultures are protease-resistant;
- to perturb prion protein expressed in the cell lines and in primary neuronal, astrocytic and microglial cell cultures by antibody to prion protein, by recombinant prion protein and by synthetic peptides corresponding to different domains of the prion protein, including a neurotoxic peptide, and
to investigate signal transduction changes by:
investigating the mechanism by which prion protein regulates intracellular calcium concentrations;
and using combined 2-D gel electrophoresis and nano-electrospray mass spectrometry to identify post-translationally modified target proteins by mass spectrometric peptide sequencing.
The successful outcome of the project will be increased understanding of pathogenic mechanisms in the TSEs and the potential identification of novel therapeutic targets to treat the human TSEs.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences health sciences public health
- medical and health sciences basic medicine neurology dementia alzheimer
- natural sciences chemical sciences inorganic chemistry alkaline earth metals
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences basic medicine pathology
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Coordinator
SE5 8AF London
United Kingdom
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