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Subproject 1

Inflammasome-associated defects of cytoplasmatic DAMP recognition - Effects of CASP1 gene mutations on transcription, cytokine release patterns and pyroptosis

Inflammasomes are multi-protein complexes that are necessary for the activation of caspase-1. Danger associated molecular patterns (DAMPs) which are recognized by the innate immune system can trigger inflammasome formation. We identified mutations in the pro-caspase-1 encoding CASP1 gene in patients suffering from recurrent febrile episodes that lead to reduced or abrogated enzymatic activity of pro-caspase-1. These mutations were absent or less frequent in healthy control populations. The mutated pro-caspase-1 variants were shown to induce more NF-κB activity via RIP2 interaction than wild type pro-caspase-1 and could thereby contribute to inflammation. The goal of the research project is to elucidate the molecular mechanisms that contribute to the manifestation of autoinflammatory disease in these patients. In particular, we want to characterize the pathways of RIP2 induced NF-κB activation by the pro-caspase-1 variants, and to examine transcriptional changes, altered cytokine secretion as well as pyroptosis in response to proinflammatory stimuli.

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Project leaders:

Angela Rösen-Wolff

Prof. Dr. med.
Angela Rösen-Wolff

Klinik und Poliklinik für
Kinder- und Jugendmedizin
Tel.: 0351-458 6870
Email: angela.roesen-wolff@
uniklinikum-dresden.de

 

Stefan Winkler

Dr. med.
Stefan Winkler
(2nd funding period)

Klinik und Poliklinik für
Kinder- und Jugendmedizin
Tel.: 0351-458 18552
Email: stefan.winkler@
uniklinikum-dresden.de

 

Joachim Roesler

Priv.-Doz. Dr. med.
Joachim Roesler
(1st funding period)

Klinik und Poliklinik für
Kinder- und Jugendmedizin
Tel.: 0351-458 6870
Email: joachim.roesler@
uniklinikum-dresden.de