MRC iCASE: Neuropeptide regulation of gastric motility as a comorbidity and diagnostic for endometriosis and pancreatic cancer

Primary Supervisor: Prof Eric O'Neill

Additional Supervision: Prof Krina Zondervan, David Church (NDM), Keaton Jones (NDSS) 

Project Overview

MRC iCASE project in conjunction with Hertility Health. Hertility health is a reproductive healthcare provider dedicated to helping women understand where they are in their fertility cycle and where there may be difficulties in convincing. Through this screening, Hertility also mediates Endometriosis signposting, polycystic ovary syndrome (PCOS) and fertility 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 commercial level.

Neuropeptides are synthesized by neurons in the brain where they function as neurotransmitters influencing psychological activity or are released into the circulation where they act as a 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 been recently 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, signalling 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 increase
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 sufficient nutrition for
homeostasis – a condition known as gastroparesis.

Pancreatic cancer is the most lethal cancer due to detection being restricted to extremely 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 neuropeptides, in particular NPS, NPY and their receptors, in the aetiology of pancreatic cancer.

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

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. Through discovery science we also aim to lay a path towards precision/stratified medicine by identifying
patients at risk.