Endocannabanoids- fine tuning enteroendocrine cell function during intestinal disease

Our guts are lined with a single layer of cells, called the intestinal epithelium, which acts as an essential interface with the external environment. This epithelium has many important functions including the absorption of nutrients, but it also acts as an efficient barrier against the plethora of resident and transient microorganisms we encounter on a daily basis. The intestinal epithelium is made up of several specialised cell types including enteroendocrine cells (EECs), which compromise just 1% of them. EECs are known to respond to nutrients by secreting peptide hormones coordinating digestion and enabling efficient nutrient assimilation. In addition to this key digestive role, we now know that EECs are the principal sensory cells of the epithelium, monitoring intestinal microbial metabolites and directly detecting pathogens. In response, EECs are able to release a unique secretome of peptides and cytokines to influence surrounding tissues. Moreover, recent reports indicate EECs are essential in maintaining the self-renewing epithelial stem cell niche during intestinal damage, linking these diverse cells with epithelial repair and cancer. Given the unique and diverse role of EECs in mediating cellular turnover, as well as responding to pathogens and our microbiome, understanding how we can influence EECs will provide potential therapeutics for diseases of the intestine such as, parasitic infection, inflammatory bowel disease and colorectal cancer. 

Novel studies have demonstrated that EECs are the unique expressers of endocannabinoid receptors. However, the signalling pathways which occur in EECs following endocannabinoid stimulation and how these interactions influence EEC secretome dynamics and epithelial turnover and repair are unknown. Utilizing enteroendocrine cell lines and intestinal organoid systems, the current best ex vivo model available, this project will define the mechanistic signalling pathways and secretome shaped during EEC detection of endocannabinoids. Identified novel therapies will then be trialled during in vivo models of intestinal disease including, helminth infection and colorectal cancer, to determine whether endocannabinoid-based therapies can modulate EEC behaviour and therefore help prevent, or treat, such diseases.

This project will benefit from a supervisory team that has combined expertise in both human and murine models of intestinal disease; providing the student with a comprehensive training in a broad range of immunological in vitro and in vivo approaches. These will include advanced flow cytometry, primary cell isolation, microbial analysis, immunohistochemistry, qPCR, cell culture, immunoassay and murine infection and cancer models.

Applications are made by completing an application for PhD Biomedical and Life Sciences October 2018 through our online application system. Closing date: midnight 28th February 2018.