FBXW7-InReg · Defining the role of FBXW7 in intestinal epithelium regeneration
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2022-09-01 → 2025-06-10
- EU contribution
- €207,312
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Defining the role of FBXW7 in intestinal epithelium regeneration
Intestinal bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a very severe disorder that affects the intestinal epithelium. The intestine gets irritated or injured often and does not heal properly, leading to a painful, sometimes infected area. In Europe, 2.5-3 million people are suffering from IBD, and unfortunately current therapies cannot restore fully the intestinal structure and function but only limit the inflammation. Over the years, it is consequently possible to identify in IBD patients the expansion of cells not behaving properly, that could also potentially cause colitis-assciated colorectal cancer (CA-CRC). It is therefore necessary and urgent to understand how we can repair completely the intestine and prevent the tumor formation. The protein FBXW7 functions as a tumor suppressor, helping to prevent the development of cancer, but is often found mutated and misfunctioning in IBD patients, potentially increasing their risk of cancer. It is not fully clear yet how these FBXW7’s mutations affect the intestine, the goal of our project is to understand the role of FBXW7 and its mutation in the reparing intestine. This is likely to help us develop novel therapies for IBD patients. When the intestinal epithelium is damaged and in need of repair, the remaing cells are able to re-acquire properties that were present in the fetal intestine. This transition is required for repairing the injured area. When the intestine is then healed, these cells modify their features again and return to the adult state as before injury. FBXW7 controls the levels of specific proteins in the cell, making sure they are broken down and removed when no longer needed or in surplus, ultimately influencing the cell behaviour. Moreover, the regulation by FBXW7 is tightly linked to the activation of specific protein kinases also involved in tissue regeneration. We hypothesise that FBXW7 regulates the return of the cells into the adult state once the tissue repair is complete, and that when FBXW7 does not function correctly or is absent because of mutations, the transition back to homeostasis is dysfunctional elevating the risk of cancer. To test this hypothesis we set the following objectives: 1. Study the effects of FBXW7 absence during intestinal repair 2. Understand the role of FBXW7 in intestinal repair 3. Identify proteins broken down by FBXW7 and modulate their abundance to rescue a non-functioning/absent FBXW7
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark
Links
Data: CORDIS, © European Union