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Interleukin-27 as a new therapy for acute severe inflammatory bowel disease

Project Description

Inflammatory bowel disease (IBD) is a debilitating, lifelong condition characterised by inflammation of the lining of the gut. The number of individuals with IBD in the UK and worldwide is increasing. Acute severe ulcerative colitis, a type of IBD, requires hospital admission due to potential life threatening complications. In 30-40% patients with this severe form, medical treatment fails, and emergency surgery with removal of the large bowel and formation of a side bag (stoma) is required. The need for life changing surgery unfolds rapidly over a few days and can be psychologically difficult to accept. There is a need for new ‘colon rescue’ medical therapies for the treatment of acute severe ulcerative colitis. We have shown in experimental models of IBD that a naturally occurring anti-inflammatory protein (interleukin-27) inhibits many aspects of the bowel immune response and aids ulcer healing of the gut lining. This project will provide the necessary link from our laboratory data to human disease. The student will define the effect of interleukin-27 on early immune responses in human colon tissues with a focus on important white blood cells (neutrophils & macrophage) that drive inflammation in acute severe ulcerative colitis. This project will provide new data on the immunosuppressive functions of interleukin-27 (IL-27) towards innate immunity in human colon tissue, offering proof-of-concept evidence for IL-27 ‘colon rescue’ therapy in acute severe colitis.

The student will define the effect of IL-27 treatment on human colonic mucosal innate inflammatory responses. Lab techniques will include explant colonic culture models with short term stimulation assays to define the effect of IL-27 on human mucosal tissue immune cells with assessment of (i) the innate immune cell subtypes involved in the IL-27 provoked response by immunohistochemistry and flow cytometry, (ii) Gene expression analysis of candidate innate inflammatory genes in colonic mucosal homogenate by real-time PCR, and appropriate protein expression validation of genes of interest and (iii) Cytokine/chemokine protein response to IL-27 in colonic mucosal homogenate and growth media by ELISA.

The student will next assess the influence of IL-27 responses in myeloid derived immune cell subsets isolated from human colon tissue with a focus on neutrophils and macrophage cells. Techniques include flow cytometry cell sorting from colon through expression of cell surface markers, isolated cell stimulation assays to measure cytokine/chemokine response and gene expression of transcription factors/inflammatory genes, exploration of specific intracellular signalling responses (by flow cytometry and Western immunoblotting) and specific cell type functions such as macrophage cell phagocytosis.

Funding Notes

This 3 year project is funded by The Cunningham Trust. The PhD Scholarship covers the cost of tuition fees, stipend and laboratory consumables.

Selection will be made on the basis of academic merit. An essential requirement is a first class or upper second honours degree in a relevant subject. A degree in immunology is desirable. Evidence of previous experience in a laboratory is essential e.g. lab based honours project or vacation scholarship.

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