Although crucial for the protection of the human body against various insults, inflammation needs
to be tightly regulated to avoid the pathological consequences resulting from an
insufficient/excessive or chronic inflammatory response. Inflammation and cell death are
interconnected cellular processes directly influencing each other. RIPK1 emerged as an essential
signalling node downstream of several immune receptors, where it functions as an adaptor
molecule that controls gene activation and as a kinase promoting cell death. The molecular
mechanism regulating the switch from “ro-survival”RIPK1 to “ro-death”RIPK1 is currently
unknown. In addition, the involvement of RIPK1 kinase-dependent death in inflammatory and
infectious diseases is currently unclear. This research proposal aims at gaining a better
understanding of RIPK1 biology by defining the molecular nature of the RIPK1 cell death checkpoint
and by revealing its physiological relevance in models of infection and disease. The research
proposal integrates studies performed at the biochemical, cellular and organism levels. We believe
that the knowledge acquired on RIPK1 with this research proposal will help identifying disorders in
which RIPK1 kinase inhibitors may provide a therapeutic advantage.