MODEL FOR ICE FEVER

"Establishing a mouse model for ICE Fever, a novel autoinflammatory syndrome associated with procaspase-1 mutations"

 Coordinatore TECHNISCHE UNIVERSITAET DRESDEN 

 Organization address address: HELMHOLTZSTRASSE 10
city: DRESDEN
postcode: 1069

contact info
Titolo: Prof.
Nome: Angela
Cognome: Rösen-Wolff
Email: send email
Telefono: +49 351 458-6870
Fax: +49-351-458 6333

 Nazionalità Coordinatore Germany [DE]
 Totale costo 100˙000 €
 EC contributo 100˙000 €
 Programma FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
 Code Call FP7-PEOPLE-2007-4-3-IRG
 Funding Scheme MC-IRG
 Anno di inizio 2008
 Periodo (anno-mese-giorno) 2008-03-01   -   2012-02-29

 Partecipanti

# participant  country  role  EC contrib. [€] 
1    TECHNISCHE UNIVERSITAET DRESDEN

 Organization address address: HELMHOLTZSTRASSE 10
city: DRESDEN
postcode: 1069

contact info
Titolo: Prof.
Nome: Angela
Cognome: Rösen-Wolff
Email: send email
Telefono: +49 351 458-6870
Fax: +49-351-458 6333

DE (DRESDEN) coordinator 0.00

Mappa


 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

autoinflammatory    mouse    mice    il    inflammation    caspase    diagnosis    syndrome    molecular    fever    periodic    pathway    acid    symptoms    heterozygous    ice    inflammasome    roles    nalp    amino    model       mutations    rip    proteolytic    autoinflammation    patients    procaspase    revealed   

 Obiettivo del progetto (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'

Introduzione (Teaser)

Molecular diagnosis is not possible for the vast majority (80/;%) of patients presenting symptoms of periodic fever. Now, research breakthroughs link this autoinflammatory syndrome with mutations occurring during protein digestion.

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