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Investigating nerve:immune cell cross talk during gut inflammation

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  • Full or part time
    Dr J Pennock
    Prof A MacDonald
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

The gut contains more nerves than any other part of the body outside the brain. These nerves contribute to pain responses and essential muscle movement, but their role during inflammation is not known. The loss of gut nerves, for instance in inflammatory bowel diseases has a huge impact on gut function but may also drive the disease. Our central hypothesis is that nerve:immune cell interaction plays a crucial role in homeostasis and resolution of inflammation in the gut. It is widely accepted that mucosal surfaces represent an actively regulated environment, although the precise mechanisms are poorly understood. This proposal builds on our recently published data, which shows that splenic dendritic cells respond to neuropeptide calcitonin gene-related marker (CGRP) with upregulation of IL-10 secretion and downregulation of activation marker CD80/86, suggesting an immunoregulatory phenotype. We have shown that CGRP+ nerves are abundant in colon, therefore we hypothesise that nerve-derived CGRP contributes to the regulatory dendritic cell/macrophage phenotype observed in the gut. Furthermore, published studies of skin and lung have indicated that a proportion of resident dendritic cells express the receptor for CGRP (RAMP1), and that their response to CGRP may prevent migration to the draining lymph node. If these functional effects hold true in the colon, this will have huge impact on our understanding of what maintains a regulated mucosal interface, and ultimately what constitutes a ‘healthy’ gut.

Training/techniques to be provided:
The project will use flow cytometry, immunohistochemistry, genomic and bioinformatics approaches to investigate the role of CGRP and dendritic cell function during colitis. The Pennock lab has expertise in gut inflammation and mouse models of colitis using genomic and transcriptomic approaches to understand molecular pathways. The MacDonald group has significant expertise in mucosal immune responses, dendritic cell biology and multi-parameter flow cytometry. The project will also take advantage of key core facilities in flow cytometry, imaging, bioinformatics and genomics, all of which have contributed to previous publications from the supervisory team.

Both supervisors are members of the Manchester Immunology Group (MIG, comprising 20 principle investigators) which has an extensive publication record and expertise in the study of cellular and translational immunology, using in vitro and in vivo approaches. This provides a stimulating and cutting edge environment for staff and students alike, maintaining high quality discussion through regular presentations, peer review and output.

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in immunology or a related area. Candidates with experience in flow cytometry and an interest in dendritic cell/macrophage biology are encouraged to apply.

This project has a Band 3 fee. Details of our different fee bands can be found on our website (https://www.bmh.manchester.ac.uk/study/research/fees/). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/).

Informal enquiries may be made directly to the primary supervisor.

References

Assas BM, Miyan JA, Pennock JL. Cross-talk between neural and immune receptors provides a potential mechanism of homeostatic regulation in the gut mucosa. Mucosal Immunol. 2014 Nov;7(6):1283-9.

Assas BM, Wakid MH, Zakai HA, Miyan JA, Pennock JL. TRPV1 expression and function in splenic dendritic cells: a potential role in immune homeostasis. Immunology 2016 Mar 147(3):292-304

Gabanyi I, Muller PA, Feighery L, Oliveira TY, Costa-Pinto FA, Mucida D. Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages. Cell. 2016 Jan 28;164(3):378-91.

de Jonge WJ. The Gut's Little Brain in Control of Intestinal Immunity. ISRN Gastroenterol. 2013 Apr 4;2013:630159.

Campaniello MA, Mavrangelos C, Eade S, Harrington AM, Blackshaw LA, Brierley SM, Smid SD, Hughes PA. Acute colitis chronically alters immune infiltration mechanisms and sensory neuro-immuneinteractions. Brain Behav Immun. 2017 Feb;60:319-332.



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