Pyroptosis is a form of programmed cell death that has been described as part of the inflammatory immune response. Sensing of pathogen associated molecular patterns (PAMPS) and/or damage associated molecular patterns (DAMPS) by immune cells triggers the assembly of canonical and non-canonical inflammasome complexes, leading to the activation of caspase-1 and human capase-4 / murine caspase-11, respectively. The activation of these caspases requires the caspase activation and recruitment domain (CARD), an interaction motif also found in the apoptotic caspases-2 and -9. Apoptosis and pyroptosis are crucial for normal cell turnover and immunity. Dysregulation of either of these pathways can result in a disturbed cellular environment leading to cancer and other disease conditions.
The objective of this project is to elucidate the function of CARD containing caspases in the pyroptotic pathway, apoptotic and other cell death pathways. Therefore we have generated a triple knockout mouse model, deficient for the CARD containing caspases-1/-11 and also -12. Since the overall contribution of caspase-12 is not very well understood, we want to initially test its contribution to the inflammatory response. Therefore we will treat these triple knockout mice with LPS and investigate the pyroptotic response. Furthermore we aim to additionally knockout the CARD containing apoptotic caspases -2 and -9 in the triple knockout model, thereby generating mice deficient for all CARD containing caspases. We will use these quint knockout mice to analyse embryonic development, inflammatory responses and the impact on the development of cancer and other diseases such as autoimmunity. In conclusion we believe that these experiments will help to elucidate the role of CARD containing caspases in the apoptotic and/ or, pyroptotic pathways and might reveal functions in other forms of cell death.