Project

Role of linear ubiquitination in intestinal inflammation and disease

Code
11PQI24N
Duration
01 November 2023 → 31 October 2025
Funding
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Other basic sciences not elsewhere classified
    • Cell signalling
    • Inflammation
    • Other medical and health sciences not elsewhere classified
Keywords
Crohn's Disease Ubiquitination immunology inflammatory bowel disease signal transduction
 
Project description

Inflammatory bowel diseases (IBD) are chronic conditions characterized by inflammation of the gastrointestinal tract. IBD patients suffer from increased intestinal epithelial cell (IEC) apoptosis and exhibit a hyperactivated NF-kB pathway leading to immune system activation and proinflammatory cytokine production. Recent studies have indicated that linear ubiquitination is a key regulatory mechanism of NF-κB signalling and cell death. Genome-wide association studies in IBD patients revealed polymorphisms in a specific E2 ubiquitin- conjugating enzyme that plays a role in linear ubiquitination. We hypothesize that linear ubiquitination could be involved in both NF-kB hyperactivation and IEC death during normal gut homeostasis and intestinal inflammation. To investigate the physiological function and mechanism of action of linear ubiquitination in IECs, we will generate IEC-specific knock-out and transgenic mice for this specific enzyme. These mice will be carefully phenotyped for the development of intestinal disease, both spontaneous and in a mouse colitis model. In addition, the mechanism of action will be studied in more detail intestinal organoids derived from these mice.