Defining the role of FBXW7 in intestinal epithelium regeneration

ended

Inflammatory bowel disease (IBD) is a severe disorder affecting millions of people in Europe, characterised by chronic flares of intestinal inflammation and causing tissue loss or malfunction. Currently, the available treatments can only reduce symptoms. New regenerative therapies promoting epithelial functionality are highly needed. Several studies report how upon damage, progenitors or more committed cells re-acquire stemness properties and foetal-like signatures to restore intestinal homeostasis. However, it is still unclear how such regenerative response is modulated and how cells revert to their adult state. Preliminary data from the host lab indicate that loss of expression of FBXW7 protein, member of a E3 ubiquitin ligase complex, reinforces cells in the foetal-like state. Interestingly, FBXW7 mutations are under positive selection in IBD patients. Thus, I propose that upon injury, cells lacking FBXW7 maintain a foetal-like state, where they are refractory to terminal differentiation, increasing the risk of aberrant tissue restoration. To test my hypothesis, I will exploit state-of-the-art in vivo and in vitro models of intestinal regeneration and make use of forefront technologies, such as CRISPR, high-content imaging, mass spectrometry and single cell RNA sequencing. This will allow me to 1. characterise FBXW7 impact on intestinal regeneration, 2. define FBXW7 mode of action in human intestinal cells, and 3. identify FBXW7 substrates as potential targets to restore tissue homeostasis. By addressing these points, it will be possible to obtain key insights into the mechanism of intestinal regeneration and identify ways to efficiently induce and control tissue repair in IBD patients, avoiding the expansion of unrestrained proliferating foetal-like cells. Importantly, leading this action, I will acquire a new set of technical and transferrable skills and reach a deep scientific maturity that will grant me a successful career as future group leader.