Project: Factors that determine RIPK1-dependent necroptosis

2018-01-01 – 2021-12-31

Abstract

When TNF is binding to TNF receptor 1 (TNFR1), the cellular outcomes can be fundamentally different: survival and pro-inflammatory signaling versus cell death signaling to apoptosis or by necroptosis. The former outcomes are initiated by receptor-associated complex I formation, while the latter outcomes are a consequence of a cytosolic complex II. In this project we want to visualize the dynamics of this complexes, especially complex II by using cellular biosensor constructs. These will be used to identify and validate the biochemical and cellular processes (Ca++, ROS, metabolism, pHi) that are crucial in the propagation of necroptosis. If we can successfully visualize these cellular outcomes, we also want to develop transgenic models in which we can score the dynamics of these processes in vivo or ex vivo. Fundamental insight in the cell biology of necroptosis regulation has important biomedical implications on the long term, to examine which pathophysiological conditions are associated with necroptosis and to develop strategies to modulate cell death outcomes by cellular and metabolic conditions rather than targeting the process itself.