RIPK1 is a master adapter/kinase downstream of many cellular stress pathways

activated by infection, cell death and cellular damage. It plays a crucial role in

survival and inflammation as well as in necrotic and apoptotic cell death signaling.

Activities of RIPK1 are tightly controlled by both post-translational modifications

(PTM; ubiquitylation, phosphorylation and proteolytic cleavage) and homotypical

RHIM domain associations. Much research has been performed on the role of

RIPK1 ubiquitylation in cell survival pathways i.e. NF-kB signaling. In this project we

will first use specific RIPK1 mutants to conduct a detailed study on the role of each

of these determinants, PTMs and RHIM domain separately on the functional

outcome in RIPK1 mediated cellular stress responses (cell survival, necrosis,

apoptosis and autophagy). Because metabolism (a.o. carbohydrate metabolism and

mitochondrial bioenergetics) is also influenced in these pathways, metabolome

studies will be performed with these RIPK1 mutants. Finally, the in vitro results will

be validated in vivo in murine cardiomyopathy models. Moreover, as inflammation,

autophagy and cell death phenomena may determine the regeneration potential of

the affected heart tissue, also the contribution of the RIPK1 determinants to

myocardial regeneration will be analyzed. The study of RIPK1 in myocardial

degeneration and regeneration will be performed in collaboration with the De Muinck

group at the University of Linköping.