1. Interrogate the effects of genetic and environmental crosstalk in the maintenance and breakdown of intestinal homeostasis.
The functional annotation of IBD risk-associated noncoding variants has been limited by their reduced penetrance, which results in subtle or immeasurable effects under steady-state conditions, suggesting that measurable effects might appear only upon exposure to environmental stressors. In particular we are working on:
– Develop novel models of intestinal inflammation.
– Generate IBD reporter zebrafish lines to investigate the function of coding and non-coding IBD risk variants.
– Identify then environmental factors and mechanism by which aberrant intestinal immune responses are triggered in genetically susceptible hosts.
– Characterize the initiation and progression of adaptive commensal-specific T cell responses.
2. Identify novel cellular and molecular mechanisms of tissue regeneration following injury.
Using unbiased analysis of the immune cell composition, microbiota and transcriptomics during intestinal inflammation and regeneration, we have identified specific immune cells, bugs and pathways that might promote tissue regeneration upon damage. In particular we are working on:
– Characterize and validate candidate genes/pathways and/or cell types with respect to their potential role(s) in tissue regeneration.
– Identify pathways that promote colorectal cancer.
– Further characterize the crosstalk between lymphocytes and the epithelium that modulate intestinal regeneration.
– Gain mechanistic insights into how lymphocytes may support barrier functions.
3. To determine the heterogeneity of UC and identify conserved genes and pathways involved in IBD.
We have recently developed an unsupervised method to molecularly stratify ulcerative colitis (UC) patients (Czarnewski et al., Nat Comm, 2019). Using this method, we have subdivided UC into two groups; UC1 and UC2. While UC1 patients are characterized by a transcriptomic signature indicating an enhanced neutrophil activity they also show poor clinical response to biological treatments. Therefore, we are working to:
– Further characterize UC1 patients and identify therapeutic targets to either promote remission or make them responders (e.g. conversion into UC2).
– Generate an affordable diagnostic tool that can be used to identify UC1 and UC2 patients.
– Further characterize UC1 and UC2 patients using other “omic” approaches (e.g. microbiome, CyTOFF, etc).
– To perform cross-species comparisons of different processes associated with IBD, such as acute intestinal inflammation and mucosal healing.