Objective
The presently proposed shared cost action between four research institutes, one within a company, aims to establish new mouse models for rheumatoid arthritis. This will be done by inserting human genes associated with rheumatoid arthritis by transgenic/homologous recombination "knock in" techniques. To advance further into understanding the basic mechanisms of RA animal models are needed. The problem is that these are in another species - the mouse - which develop disease due to mouse specific genes and structure. By exchanging the major genes with their human counterparts with knock in techniques we hope to establish humanized mouse models useful for further research on the human disease. This will lay the ground for development of new antigen-specific therapeutic strategies addressing the disease causing specific autoimmune recognition of the joints.
Such a goal is of high priority. Rheumatoid arthritis is an endemic disease affecting 1 % of the population causing major human suffering and high socio-economic costs. It is a chronic inflammatory disease involving an autoimmune inflammatory attack on cartilagenous diarthrodial joints. The current therapy is based on analgesic and anti-inflammatory drugs. Although recent development of anti-inflammatory treatment is promising it does not change the disease course or the chronic destructions of the joints. In addition, all anti-inflammatory treatment, if effective, will also as a side-effect diminish the patients ability to combat infections and tumors.
The goal to identify the structures on cartilage proteins recognized by the immune system and to insert the disease associated human genes in mice, will be achieved through a cooperative approach by groups which already are in close collaboration and have demonstrated the feasibility of this approach by identifying the major cartilage type II collagen peptide (CII260-270) as bound by both mouse and human MHC class II molecules conferring inherited susceptibility to chronic arthritis.
The following specific objectives will be pursued in this SCA
- Establishment of mice expressing human DR4 structures in the first domains of the endogenous class II molecules. The first domains will be modified to express either RA associated sequences (0401) or RA protective sequences(0402).
- To structurally determine the major T and B cell epitopes on cartilage-type II collagen (CII) of importance for development of arthritis and to apply the knowledge using new mouse strains mutated in the epitopes.
- To establish humanized mouse models by crossbreeding mice with human DR4 molecules, humanized cartilage collagens and gene regions outside of MHC,identified in gene mapping projects.
- To develop new antigen-specific therapeutic techniques for treatment of arthritis using the new mouse models with purified triple helicalglycosylated collagen peptides.
The proposed action will yield (1) new humanized experimental animal models for RA, (2) important information concerning disease pathogenesis and (3) lay the ground for future antigen specific therapies of RA.
This knowledge will be channeled into European pharmaceutical industry and will eventually lead to lower socio-economic costs and reduction of human suffering from an endemic disease.
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 clinical medicine rheumatology
- medical and health sciences health sciences inflammatory diseases
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences basic medicine immunology
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Coordinator
8200 AARHUS C
Denmark
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