About the Project
Gut-derived peptide hormones regulate a large number of metabolic processes, and there is great interest in exploiting their effects to treat disease. The blockbuster anti-obesity agent semaglutide, based on modifications of the gut hormone glucagon-like peptide-1 (GLP-1), exemplifies this approach. Several other appetite-regulating gut hormone systems are being successfully developed to augment weight loss and metabolic improvements alongside GLP-1, for example GIP, amylin and peptide YY.
Our laboratory is focussed on understanding how gut hormones activate their receptors and how this information can be used to design better drugs. Our approach has led to the development of several clinical candidates, with five entering phase I trials, one in phase II and one in phase III. A particular focus is “biased agonism”, a pharmacological paradigm that describes how different agonists for the same receptor can show different preferences for downstream signalling pathways. We have shown that bias between G protein pathways and β-arrestin recruitment can influence the therapeutic efficacy of GLP-1 receptor agonists.
In this project the aim is to investigate the impact of coding mutations in gut hormone systems on receptor biology, physiological responses and therapeutic efficacy. Receptor systems of interest are as listed above, i.e. GLP-1, GIP, amylin and PYY. The student will be trained in modern pharmacological in vitro techniques, including cell-based signalling assays, high-throughput and high-resolution fluorescence microscopy, genetic manipulation and primary cell models. In vivo work will include development of transgenic mice and metabolic testing in rodents. The broad range of techniques and strong translational application will provide a strong platform for a future career in academia or industry.
Potential applicants with a strong background in pharmacology, molecular biology, biochemistry or related subjects are encouraged to contact Ben Jones to discuss the opportunity (ben.jones@imperial.ac.uk).
Bursary: £25,000 (Home students only)
