Objective
In up to 80% of patients with symptoms of an autoinflammatory syndrome (periodic fever syndrome) a molecular diagnosis is currently not possible. Procaspase-1 (aka IL-1 converting enzyme, ICE) is a component of the CIAS1/NALP3 ‘inflammasome’ and plays critical roles in releasing the proinflammatory cytokine IL-1b. and regulating the NFkB-activating RIP-2 pathway. Sequencing of the procaspase-1 coding region from 200 patients with undiagnosed autoinflammatory syndromes revealed mutations in 8 patients, 7 of whom were heterozygous. The autoinflammatory syndrome associated with these mutations has tentatively been termed ‘ICE Fever’. X-ray crystallography and functional studies revealed that the resulting amino acid changes destabilize interactions within the interface of the mature caspase-1 tetramer and thus reduce proteolytic activity and IL-1b release. One consequence is an overactivity of the pro-inflammatory RIP-2 pathway due to diminished proteolytic inactivation of RIP-2 by caspase-1, potentially leading to autoinflammation. We propose to establish a mouse model for ‘ICE Fever’ by generating transgenic mice in which a single amino acid substitution in the active center has abolished the proteolytic activity of procaspase-1. For transgenesis, a novel ‘switch dual color’ vector will be used that allows to reproduce the wild type, heterozygous and homozygous states. Mice will be monitored in detail for the development of signs, symptoms and laboratory abnormalities suggestive of autoinflammation. Monosodium urate crystals, which are known to activate the NALP3 inflammasome, and the murine air pouch model of inflammation will be used to test for a possible exaggerated innate immune response. This will be the first mouse model for an inflammasome-associated autoinflammatory syndrome. It may afford new insights into the pathogenesis and treatment of ‘ICE Fever’ and into the roles of procaspase-1 and the RIP-2 pathway in inflammation in gener
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.
- engineering and technology materials engineering colors
- natural sciences earth and related environmental sciences geology mineralogy crystallography
- medical and health sciences basic medicine immunology
- natural sciences biological sciences genetics mutation
- natural sciences chemical sciences organic chemistry amines
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2007-4-3-IRG
See other projects for this call
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
01069 DRESDEN
Germany
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.