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

Lead supervisor: Prof. Eric O'Neill 

Co-supervisor: Prof. Krina Zondervan, Prof. Christian Becker

Commercial partner: Hertility health

 

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(1).

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, e.g Pancreatic Polypeptide, PP. Importantly, NPS and NPY have been implicated in influencing gut motility. Aberrant levels of NPS/NPY have been described to increase CCK and Somatostatin levels which are described to prevent pyloric sphincter opening and reducing stomach-duodenum peristalsis (2). 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(3,4). There is increasing interest in neuropeptides and their receptors in the aetiology of pancreatic cancer and we have identified that patients expressing high levels of NPSR1 have a poor rate of survival.

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.

1. Sci Transl Med. 2021 Aug 25;13(608):eabd6469
2. Gastroenterology. 2010 Jan;138(1):98-107.e4
3. Gastroparesis and Cancer-Related Gastroparesis. 2019. doi.org/10.1007/978-3-319-77740-5_114
4. Pancreatic carcinoma is associated with delayed gastric emptying. Dig Dis Sci 1986;31:265–7

 

Apply using course: DPhil in Oncology

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