A4 Phenotypic characterization of mutated procaspase-1 variants in autoinflammation


PRINCIPAL INVESTIGATOR
AND CO-INVESTIGATORS
OF THE SUBPROJECT

Bild von Prof. Dr. med. Rösen-Wolff

Angela Rösen-Wolff

Angela Rösen-Wolff, Prof. Dr. med.
Dept. of Pediatrics
University Clinic Carl Gustav Carus
Fetscherstr. 74, 01307 Dresden
Phone: +49 351 458-6870
Fax: +49 351 458-6333
E-Mail: Angela.Roesen-Wolff@uniklinikum-dresden.de

Bild von PD Dr. med. Roesler

Joachim Roesler

Joachim Roesler, PD Dr. med.
Dept. of Pediatrics
University Clinic Carl Gustav Carus
Fetscherstr. 74, 01307 Dresden
Phone: +49 351 458-6870
Fax: +49 351 458-6333
E-Mail: Joachim.Roesler@uniklinikum-dresden.de

Bild von Prof. Dr. med. Gahr

Manfred Gahr

Manfred Gahr, Prof. Dr. med.
Dept. of Pediatrics
University Clinic Carl Gustav Carus
Fetscherstr. 74, 01307 Dresden
Phone: +49 351 458-6870
Fax: +49 351 458-6333
E-Mail: Manfred.Gahr@uniklinikum-dresden.de


TITLE OF SUBPROJECT

Phenotypic characterization of mutated procaspase-1 variants in autoinflammation


CONDITION/TOPIC

Autoinflammatory diseases


OBJECTIVE(S)

To address the principal question of how defects of the innate immune system contribute to autoinflammation. The primary goal is to understand the contribution of procaspase-1 variants with reduced or abrogated enzymatic activity to the autoinflammatory phenotype of patients suffering from recurrent febrile episodes with generalized inflammation. We expect to understand the influence of procaspase-1 variants on (i) pro-inflammatory cell death (pyroptosis), (ii) autophagy mechanisms , and (iii) type 1 interferon production following TLR activation.

SUMMARY

Autoinflammatory diseases are caused by deregulated processes of the innate immune system. We have recently identified an autoinflammatory impact of mutations in the CASP1 gene, encoding the proinflammory caspase-1 enzyme. The mutations decreased the enzymatic activity of procaspase-1, but strongly activated NF-kB via RIP2. These studies provided novel insight into the role of NFkB activation in autoinflammatory diseases. The aim of the current proposal is to identify additional mechanisms induced by the mutations, which contribute to autoinflammation such as proinflammatory cell death (pyroptosis), autophagy and type 1 interferon responses to bacterial infections. A better understanding of the pathophysiology of autoinflammatory diseases will help to establish rapid diagnoses and to develop innovative and efficient treatment strategies.