MODEL FOR ICE FEVER · Establishing a mouse model for ICE Fever, a novel autoinflammatory syndrome associated with procaspase-1 mutations
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2008-03-01 → 2012-02-29
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-IRG
Линиите свързват координатора с партньорите.
Накратко на български
Генетичните мутации при редкия синдром „ICE fever“ се изследват чрез създаване на мишки с подобни дефекти в ензима про-каспаза 1. Това помага за разбирането на развитието на болестта и тестването на нови терапии за подобряване на лечението.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Establishing a mouse model for ICE Fever, a novel autoinflammatory syndrome associated with procaspase-1 mutations
Background. ICE fever is a rare human disease that is caused by loss of function mutations in the gene encoding pro-caspase 1 (aka ICE, interleukin 1 converting enzyme), the enzyme responsible for activation and release of IL-1beta. Clinically, it is characterized by chronic autoinflammation, manifesting as recurrent fevers, exanthema, increased inflammatory markers, and dysfunction of the musculoskeletal system. It has not been possible to rationally design treatment strategies for ICE fever because of the lack of understanding of its pathogenesis. The aim of the project was to generate a mouse model for ICE fever by establishing transgenic mice expressing pro-caspase 1 variants that recapitulate the effects of the mutations found in patients with ICE fever. Results. A transgenic mouse line expressing the Casp1C284A allele, which destroys the active center of the enzyme, was generated with ET-cloning. Genetic characterisation confirmed the presence of the transgene in the absence and / or presence of a wild-type Casp1 allele. Preliminary experiments with this Casp1C284A line demonstrate that, while IL-1beta release is impaired as expected, mononuclear cells from these mice clearly possess a hyperinflammatory phenotype, as evidenced by increased release of IL-6 and TNF alpha after stimulation with LPS. A complete immunological characterization of these mice is underway. Conclusions. A mouse model for ICE fever is being established. Once immunological characterization has been completed, this model will not only improve our understanding of the pathogenesis of ICE fever and related autoinflammatory disorders but also allow testing various hypothesis-based therapeutic interventions, which will likely include inhibition of IL-6 and TNF alpha. Improved treatments will benefit the afflicted individuals by improving their quality of life but also society at large by reducing days of work loss and health care expenses resulting from disease flares.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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
Оригинален текст от CORDIS (на английски).
Участници
- TECHNISCHE UNIVERSITAET DRESDEN · DresdenКоординаторГермания
Връзки
Данни: CORDIS, © Европейски съюз