Elucidating the interactions between the immune and the epithelial compartments in Inflammatory Bowel Disease using mini-guts

The maintenance of intestinal homeostasis depends on the interactions between several compartments including the gut epithelium, the intestinal microbiota and the gut-associated immune system. Disrupting this delicate balance results in intestinal inflammation, which is associated with several diseases such as Inflammatory Bowel Disease (IBD), cancer and neurodegenerative diseases.

We developed a novel system of lymphocyte cultures in intestinal organoids (“mini-guts”) that mimics the intestinal environment (Figure-1). Intestinal organoids are generated from intestinal stem cells that differentiated into the several types of intestinal epithelial cells forming intestinal crypts. This pioneer system led us to identify novel roles for innate lymphoid cells (ILC) (Jowett et al, under revision) in regulating intestinal epithelial cells and fibroblast proliferation and function. To facilitate the translation of our discoveries our co-culture system is established with human cells allowing us to use patients’ cells to test the importance of our novel pathways in the clinical setting and the potential to modulate these pathways to promote health.

The overall aim of this project is to identify key pathways responsible for the crosstalk between intestinal epithelial cells and lymphocytes in the context on intestinal associated diseases. We are particularly interested in exploring non-classical roles of Innate Lymphoid Cells, which we have recently identified (Jowett et al, under revision), in the promotion of intestinal epithelial cell regeneration and in the development of intestinal fibrosis.

Year 1: Use co-cultures of lymphocytes with intestinal organoids to identify potential pathways that govern the interaction between these cells (e.g. RNA-seq/scRNAseq).
Year 2: Validate the pathways identified (e.g. CRISPR/Cas9 technology).
Year 3: Modulate the new pathways using pharmacological approaches (drugs) using patient cells.

During this project the student will acquire a wide range techniques such as flow cytometry, imaging, molecular biology (including CRISPR), transcriptomics, single cell RNAseq, epithelial, lymphocyte and stem cell biology and mucosal immunology techniques.