Defining the cellular and molecular architecture of intestinal regeneration following acute inflammation

Harnessing the power of tissue regeneration to promote resolution in chronic autoimmune diseases such as ulcerative colitis (UC) is a promising approach, as mucosal healing predicts sustained remission.

However, uncontrolled regeneration may lead to tumor growth, highlighting the need to identify pathways unlinking regeneration and tumorigenesis.

My lab has identified liver X receptor (LXR) pathway whose activation promotes intestinal regeneration while inhibiting tumorigenesis in vivo. How LXR unlinks regeneration and tumorigenesis is not known.

Using pharmacological tools and genetically engineered mouse models, we will first investigate the mechanisms how LXR activation promotes mucosal healing and inhibits tumor growth. Additionally, we have stratified UC patients into two novel subtypes namely UC1 and UC2.

Since the UC1 profile is associated with increased tissue injury and poor response to therapies, we will test whether the stratification into UC1 and UC2 depends on the degree of tissue damage and capacity to heal.

Using single-cell transcriptomics, we will generate an atlas of tissue regeneration in UC1 and UC2 patients and test if organoids from UC1 patients display signs of mucosal healing upon LXR activation.

We will complement our studies with organoid-immune/stromal co-culture to test the positively identified pathways (eg LXR).

This will pave the way towards personalized medicine in UC by identifying novel targets for boosting safer regeneration in UC patients.