MRC iCASE project – Neuropeptide regulation of gastric motility as a comorbidity and diagnostic for endometrosis and pancreatic cancer

Neuropeptides are synthesized by neurons in the broain where they function as neurostransmitters influencing psychological activity or are released into the circulation where they act as neurohormones to regulate numerous physiological processes. They are also expressed in tissues of the body, where they feedback information on local activity in tissues to the brain. They relay pain signals and have recently been identified as a main driver of heightened pain attributed to endometriosis through upregulation of Neuropeptide S (NPS) and its receptor NSPR1.

Neuropeptide signalling is also central to the gut-brain axis that controls gut motility, sinalling when the stomach becomes full and controlling the timing of gastric emptying into the duodenum via CCK and GLP1. Subsequently, the duodenum senses food transit and stimulates the pancreas to release digestive enzymes into the gut. Importantly, NPS and NPY have been implicated in influencing gut motility. Aberrant levels of NPS/NPY have been described to increas CCK levels preventing pyloric sphincter opening and reducing stomach peristalsis. Failure of stomach emptying and retaining undigested food increases reflux, vomiting and limits the ability of the body to receive sufflicient nutrition for homeostasis – a condition known as gastroparesis.

Pancreatic cancer is the most lethal cancer due to detection being restricted to extemely advanced symptoms. However, patients frequently describe pain and digestion issues years prior to diagnosis with >60% pancreatic cancer patients suffering from gastroparesis by the time treatment starts. There is increasing interest in neurpeptides, in particular NPS, NPY and their receptors, in the aetiology of pancreatic cancer.

Emerging evidence suggests that gastroparesis is consident with both endometriosis and pancreatic cancer and we want to investigate the role of NPS/NPSR1 in gut motility, exploring genetic traits of neurpeptide signalling and gastroparesis as early indications of aberrant neurpeptide signalling with the potential for interviention to ameliorate symptoms.

Hertility Heather is a reproductive healthcare provider dedicated to helping women understand where they are in their fertility cycle and where there may be difficulties in conceiving. Through this screening, Hertility also mediates Endometriosis signposting, polycystic ovary syndrome (PCOS) and fetility hormone imbalance through a combination of genetics and blood analysis. Their computational framework and bioinformatics pinpoint female physiological cycles and they have gathered a large number of customers that have struggled to get diagnosed with endometriosis. Hertility will provide training and commercial experience in screening for translation at a commerical level.

Training Opportunities

The student will get training in pre-clinical pancreatic models (EON, Oncology), endometriosis and gut physiology from NDM. As the project undertakes investigation in model systems and human tissue to identify mechanisms of pathophysiology, and to demonstrate proof-of-concept evidence for neuropeptide receptor intervention in gastroparesis and pain as a comorbidity of cancer and endometriosis, this falls under the MRC health focus theme of advanced therapies. Furthermore through discovery science we aim to lay a path towards precision/stratified medicine by identifying patients at risk.

Enquiries

pgr@oncology.ox.ac.uk

ian.tomlinson@oncology.ox.ac.uk

https://www.ox.ac.uk/admissions/graduate/courses/dphil-oncology