Nuclear factor-kB (NF-kB) is a transcription factor that plays an essential role in innate and adaptive immunity, inflammation and development. NF-kB-dependent gene expression and apoptosis play crucial roles in numerous cellular processes, and defects in their regulation contribute to a variety of diseases including inflammatory and autoimmune diseases, neurological disorders and cancer. A20 is a cytoplasmic zinc finger protein that has been characterized as a dual inhibitor of NF-kB activation and apoptosis. Mice deficient for A20 develop severe inflammation and cachexia, are hypersensitive to LPS and TNF, and die prematurely. In vivo experiments using conditional gene knockouts or knockins of potentially important mutants are critically important for evaluating the role of a factor in physiological and pathological conditions.
The aim of this Marie Curie ERG-project is to understand the function, activation and regulation of NF-kB activation by A20, using conditional gene targeting in the mouse. More specifically, I would like to, 1. investigate the physiological role of A20 by generating mice with conditional alleles for the A20 gene allowing deletion of the protein, 2. generate mice which are mutated in the recently described ubiquitin-editing domains of A20, and 3. generate a knockin A20-TAP fusion mutant which would allow me to identify the binding partners of A20 in different tissues and/or upon stimulation with known activators of the NF-kB pathway and/or in specific disease states.
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