UNIVERSITÄT ZU KÖLN

Abstract

The plasticity between different forms of programmed cell death, in particular apoptosis, necroptosis and pyroptosis, is crucially important for tissue homeostasis and repair following different types of insults, such as pathogenic infection or injury. However, the mechanisms controlling such plasticity are only starting to be understood.  Here, we want to investigate the cross-talk between apoptosis, necroptosis and pyroptosis, its regulatory mechanisms and relevance to tissue homeostasis and repair. One of the signalling nodes that plays a key role in the regulation of these three forms of cell death is represented by the heterodimer composed of Caspase-8 and cFLIP long (here referred to as cFLIP). Although cFLIP has long been known as regulator of Caspase-8 activity, the mechanisms by which cFLIP does so are still poorly understood. In this project, we will use a newly generated, as well as already existing models of genetically altered mice to understand the function of cFLIP in the regulation of Caspase-8 activity and the role of cFLIP for the ability of Caspase-8 to orchestrate different types of cell death. The findings coming from this research proposal will help understand how cells coordinate different cell death programs and their pathophysiological role. 

Veli Ö, Kaya Ö, Varanda AB, Hildebrandt X, Xiao P, Estornes Y, Poggenberg M, Wang Y, Pasparakis M, Bertrand MJM, Walczak H, Annibaldi A, Cardozo AK, Peltzer N. RIPK1 is dispensable for cell death regulation in β-cells during hyperglycemia. Mol Metab. 2024 Jul 12:101988. doi: 10.1016/j.molmet.2024.101988. Epub ahead of print. PMID: 39004142.

Kelepouras K, Saggau J, Varanda AB, Zrilic M, Kiefer C, Rakhsh-Khorshid H, Lisewski I, Uranga-Murillo I, Arias M, Pardo J, Tonnus W, Linkermann A, Annibaldi A, Walczak H, Liccardi G. The importance of murine phospho-MLKL-S345 in situ detection for necroptosis assessment in vivo. Cell Death Differ. 2024 May 23. doi: 10.1038/s41418-024-01313-6. Epub ahead of print. PMID: 38783091.