Project

Unraveling the in vivo role of RIPK1: Physiological and pathological consequences of kinase-dependent and kinase-independent functions 

Duration
01 January 2016 → 31 December 2019
Funding
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Other biological sciences
Keywords
RIPK1 protective function
 
Project description

Recently we published on the protective role of RIPK1 signaling in keeping the intestinal barrier intact (Takahashi et al. Nature 2014). Removal of RIPK1 in intestinal epithelial cells results in a profound spontaneous inflammatory phenotype due to enhanced induction of cell death. The phenotype was rescued in RIPK1 kinase dead knockin mice, demonstrating that the scaffold function and not the kinase function of RIPK1 is implicated in the survival of intestinal epithelial cells (IEC). In this project we have three major goals. First we want to explore the molecular mechanism of this protective function of RIPK1 by reconstituting RIPK1 mutants in organoids in order to identify the critical residues or phosphorylation sites of RIPK1 involved in survival of IEC. Second, we want to use the spontaneous phenotype of inflammation in RIPK1 knockout and a model of necrotizing enterocolitis (NEC) to explore the role of phagocytosis as an inflammation resolving mechanism using drugs that stimulate phagocytosis or using transgenic models with increased phagocytosis. Finally, as leukocytes (T cells and macrophages) play an important role in the homeostasis of the intestine, we also want to study the survival role of RIPK1 in these cells. This project may form the basis to develop strategies to increase the RIPK1 survival function by small compounds. But first we need profound mechanistic insights on the survival role of RIPK1 and its mechanism of action.