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Neuroimmune mucosal pathogenesis in gastro-oesophageal reflux disease


Blizard Institute

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Dr P Woodland , Prof D Kelsell , Dr D Blaydon , Dr Madusha Peiris No more applications being accepted Funded PhD Project (UK Students Only)
London United Kingdom Immunology Molecular Biology Neuroscience Pharmacology

About the Project

Up to 20% of Western populations suffer from gastro-oesophageal reflux disease (GORD), typically causing symptoms of heartburn and regurgitation. In 70% of these cases the macroscopic appearances of the oesophagus are normal, with no erosion or obvious inflammation (non-erosive reflux disease, NERD). The standard therapy for GORD is proton pump inhibitor (PPI) therapy. Many patients come to secondary care due to lack of response to PPI, and indeed 30%-40% of patients with GORD do not respond adequately to current therapy. This has a significant impact on quality of life and healthcare costs.

Oesophageal sensation is determined by factors in the oesophageal mucosa, the intrinsic and extrinsic innervation and a central nervous system processing. We believe that mucosal mechanisms are of fundamental to heartburn perception. The oesophageal mucosa is the first line in contact with stimuli such as acid and non-acid reflux. We, and others, have investigated the role of mucosal abnormalities in generation of pathological oesophageal sensation, and better understanding may lead to better and novel therapies.

The oesophageal mucosa nociceptive afferent nerve fibres. It appears that the distribution of these fibres is altered in disease states. Associated with these neurones (and on the epithelial cells themselves) are several receptors that may act as transducers of painful stimuli. These include a number of acid- (e.g. TRPV, ASIC), bile acid- (TGR, FX5) and stretch-sensitive (e.g. TRPA1) ion channels, as well as inflammatory mediators and pain transducing (e.g. Nav 1.8) receptors.

This PhD aims to develop this knowledge to understand better how the mucosa reacts to acid exposure and inflammation in gastro-oesophageal reflux disease. Using ex vivo human oesophageal biopsies, we aim to:

1.      Evaluate the presence of inflammatory receptors on acid-sensing nerves in the oesophageal mucosa of patients with gastro-oesophageal reflux disease.

2.      Assess the association of immune cell subtypes with sensory neuronal populations in reflux disease.

3.      Assess the effect of pharmacological manipulation on mucosal inflammatory response to acid exposure.

Techniques used by the PhD student are likely to include immunohistochemistry, polymerase chain reaction release assays, Ussing chamber studies.


Funding Notes

This studentship is funded by an unrestricted, investigator-led industry grant and will commence in September 2021. 3 years of funding (£17,285 per annum) and UK PhD fees are included.
Applications. Please apply using this link: https://mysis.qmul.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RFQM-W1XF-09&code2=0012

References

Ustaoglu A, Nguyen A, Spechler S, Sifrim D, Souza R, Woodland P. Mucosal pathogenesis in gastroesophageal reflux disease. Neurogastroenterol Motil. 2020:e14022.
Woodland P, Shen Ooi JL, Grassi F, Nikaki K, Lee C, Evans JA, et al. Superficial Esophageal Mucosal Afferent Nerves May Contribute to Reflux Hypersensitivity in Nonerosive Reflux Disease. Gastroenterology. 2017;153(5):1230-9.
Woodland P, Batista-Lima F, Lee C, Preston SL, Dettmar P, Sifrim D. Topical protection of human oesophageal mucosal integrity. Am J Physiol Gastrointest Liver Physiol. 2015;308(12):G975-80.
Woodland
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