Identifying a Wnt pathway inhibitor for stem cell maintenance in IBD

Inflammatory bowel disease (IBD) represents a major healthcare burden which affects approximately 5 million people worldwide. Ulcerative colitis (UC) is one of the main forms of IBD which affects the colon (large bowel). The colon becomes inflamed with ulcers on the inner lining of the bowel which leads to acute and severe abdominal pain, persistent diarrhoea, nausea, fatigue, and fever. In severe cases an urgent operation may be necessary. This is a chronic (long lasting) condition but when the treatment is effective there will be periods when a patient will be symptom free. Unfortunately, less than half of UC patients do not show response to current therapies. Additionally, UC patients exposed to chronic inflammation have a 1 in 3 lifetime risk of colorectal cancer. So, there is an urgent need of more successful treatments to improve patient's quality of life and outcome.

In IBD patients the inflamed intestinal tissue fails to repair because chronic inflammation reduces the intestinal stem cell population which is responsible for tissue reparation. My lab has found a protein responsible to modulate the number of cells that are responsible to replace damage cells during chronic inflammation. In our project, we aim to discover novel effective approaches for treating IBD patients by inactivating this protein. First, we will study its mechanism of action and second, we will test blocking antibodies (i.e. inactivation of this protein). This will let us know if we can improve tissue regeneration and in consequence, decrease inflammation. We will use UC human samples from patients and healthy volunteers that will be cultured in an in vitro innovative 3D organoid model that will help us to understand the mechanism driving the disease forward and how to improve tissue repair. Our findings will be translated into improved treatments and will help improve IBD patient's health.

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Inflammatory bowel disease (IBD) represents a major healthcare burden which affects approximately 5 million people worldwide. Ulcerative colitis (UC) is one of the main forms of IBD which affect the colon and rectum. UC involves several aberrations as defects in epithelial barrier function, overactivated host defence pathways, atypical immune regulation, and failing tissue repair. Unfortunately, less than half of UC patients do not show response to current therapies (e.g. anti-TNF agents). Additionally, UC patients exposed to chronic inflammation and in consequence to active tissue regeneration have a 1 in 3 lifetime risk of colorectal cancer. So, there is an urgent need of more successful treatments.

In IBD the inflamed intestinal tissue fails to repair because chronic inflammation reduces the intestinal stem cell population which is responsible for tissue reparation. Intestinal stem cells modulated by Wnt pathway are capable of self-renew as well as produce more specialized progenies to replace damaged cells. We have found that a novel Wnt inhibitor which is upregulated in intestinal inflammation, decreases stem cell activity and in consequence impairs tissue regeneration. These findings were confirmed by using mouse models and murine 3D-organoids.

In this project, we aim to discover new mechanisms to re-activate stem cells by blocking this protein function. We will study its mechanism of action; we will find the unknown receptor and we will test blocking antibodies. Our findings will characterize the mechanism of inhibition in attenuating the inflammatory response by using an innovative human UC enteroid model derived from patient's samples and healthy volunteers. Despite ongoing efforts in mouse models, clinical paradigms in IBD are still imprecise and human 3D organoids will help to understand basic mechanisms driving the disease forward and test treatment's efficiency. In conclusion, we aim to discover a novel therapeutic approach for UC patients.