Objective
In human demyelinating diseases like multiple sclerosis (MS), inflammatory reactions are the primary cause of myelin damage. While experimentally-induced animal models for MS have provided much insight into the involvement of myelin- specific T-cells in the early phases of disease, the peripheral immune response alone is unable to account for the widespread and selective destruction of myelin that occurs in MS and that leads to impairment of neurological function.
A critical additional pathogenic factor, for which characterised animal models have not yet been developed, relates to disturbances of the cellular and molecular environment within the central nervous system (CNS) itself, for example by the deregulated production of pro-inflammatory molecules by activated glia. Tumour necrosis factor a(TNF)is a major effector molecule of the immune- system, and is now believed to play a critical role in the pathogenesis of MS and several other neuroinflammatory and neurodegenerative CNS diseases such as AIDS dementia and Alzheimer's disease. We have recently demonstrated that TNF overexpression in the CNS of transgenic mice, can indeed trigger a spontaneous inflammatory demyelinating disease with many of the clinical and histopathological hallmarks of MS. To further develop this phenotype as a model for human CNS inflammation and demyelination, major questions concerning the molecular and cellular mechanisms by which TNF triggers disease need to be addressed. The core of the present proposal centres around the development and application of state-of-the-art techniques in transgenic and conditional gene targeting methodology, to introduce specific disturbances into the micro- environment of the CNS, as an approach to generate animal models of human CNS disease with precise genetically determined characteristics. As well as specifically addressing questions about TNF biology, such as the source and context of deregulated TNF production, the cellular distribution of the two high affinity TNF receptors (pSSTNFR & p75TNFR) and the results of their respective signalling, this approach will also be used to study the contribution of additional factors that might predispose the CNS to inflammation and demyelination, particularly metabolic disturbances in myelin, and disturbances in the function of the blood-brain barrier.
The goals of this proposal are:
1. To develop new predictive animal models of human inflammatory, demyelinating and neurodegenerative diseases of the CNS, by the use of gene addition, gene deletion and conditional gene targeting protocols, to create specific perturbances in cellular homeostasis (i.e. disruption of the blood-bra barrier), cytokine balances (i.e. TNF and TNF-R production) and/or the molecular composition of myelin (i.e. PLP protein).
2. To exploit the molecular and cellular phenotypes of these in-vivo systems and of the pathologies induced, to gain further insight into the biology of CNS immune response, and into the pathogenic mechanisms leading to the development of the relevant human diseases.
3. To use the transgenic animal models to identify key mechanisms as potential targets for therapeutical intervention, and to design and test, in-vivo, new therapies and pharmacological approaches aiming to control the induction and perpetuation of destructive inflammatory phenomena in the CNS (many of these will be provided by Industry).
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 basic medicine neurology dementia alzheimer
- medical and health sciences basic medicine neurology multiple sclerosis
- medical and health sciences basic medicine immunology
- medical and health sciences health sciences infectious diseases RNA viruses HIV
- medical and health sciences basic medicine physiology homeostasis
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Coordinator
11521 ATHENS
Greece
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