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MRC DTP 4 Year PhD Programme: Defining the signalling pathways regulating intraepithelial lymphocytes in the gut


About This PhD Project

Project Description

This project is offered as part of the University of Dundee 4-year MRC DTP Programme “Quantitative and Interdisciplinary approaches to biomedical science”. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science. The outstanding biomedical research at the University of Dundee was recognised by its very high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK. A wide range of projects are available within this programme crossing exceptional strengths in four key areas: Infection and Disease; Responses to Cellular Stresses; Development, Stem Cells and Neurobiology; and Big Data and Translation. All students on this programme will receive training in computational biology, mathematical biology and statistics to equip with the quantitative skills in tackling complex biological questions. In the 1st year, students will carry out 3 rotation projects prior to selection of the final PhD project.

Intraepithelial lymphocytes (IEL) are the first immune cells that pathogens encounter in the gut. These T lymphocytes lie within the epithelial layer, and are central to controlling infection, stress or transformation of the gut epithelium. At the same time, deregulation of IEL responses can lead to inflammatory bowel diseases such as Coeliac and Crohn’s disease. Despite their importance, we have a poor understanding of how IEL sense and respond to stress and infection of the intestinal epithelia, and how they maintain their quiescence in the presence of the normal gut microflora. The aim of this project is to gain a systems-level overview of the signalling pathways that regulate IEL function. The student will use state-of-the-art phosphoproteomics, single cell phospho-and epigenetic-profiling through high-content cytometry, and computational analyses, to get a global overview of the dynamic changes that occur in IEL during intestinal infection. The student willaddress the relevance of identified signalling pathways for IEL functionin vivoby studying infection of mice with oral pathogens, germ-free mouse models, and genetically modified systems.The student will work collaboratively with the laboratories of Dr.Swamyand Dr. Moraga, working in the MRC Protein Phosphorylation and Ubiquitylation unit, one of the world’s leading centres studying the roles of signal transductionin health and disease.The student will have the opportunity to learn in vivoand in vitro immunological techniques, proteomics, big data analyses, use of relevant software such as R, Bioconductor, high throughput single-cell analyses in a dynamic and collaborative environment.


References

Recent work from the labs can be found in the following references:

Chen Y, Newton IP, Vandereyken M, Moraga I, Nathke IS, Swamy M(2019). Loss of Adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22. Preprint-BioRxiv. doi: https://doi.org/10.1101/479972.

Swamy M, Beck-Garcia K, Beck-Garcia E, Hartl FA, Morath A, Yousefi OS, Dopfer EP, MolnárE, Schulze AK, Blanco R, Borroto A, Alarcon B, Höfer T, Minguet S, Schamel WW (2016). “A cholesterol-based allosteric model of T cell receptor phosphorylation” Immunity, 44(5):1091–101.

Martinez-Fabregas J, Wilmes S, Wang L, Hafer M, Pohler E, Lokau J, Garbers C, Cozzani A, Piehler J, Kazemian M, Mitra S, Moraga I(2019).Kinetics of cytokine receptor trafficking determine signaling and functional selectivity Preprint-BioRxiv. doi: http://dx.doi.org/10.1101/638031.

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