Characterising target organ destinations of GLP-1 receptor agonists and related peptides using mass spectrometric techniques
Summary
GLP-1 and GIP, which form the basis for the new classes of injectable weight loss drugs, are just 2 of more than 20 peptide hormones produced by the intestinal epithelium. Despite the recent therapeutic successes of synthetic agonist peptides containing GLP-1 and GIP sequences (Wegovy and Mounjaro), there are many remaining questions about the biology of these native peptides and their injectable analogues.
Understanding how these hormones are secreted after a meal, and which organs are targeted by the native hormones and their injected analogues, is crucial for further development of drugs for obesity and other metabolic and gastrointestinal conditions. Detecting native gut peptides and their therapeutic derivatives (which are often acylated and sequence-modified) can be challenging and require specialised methods such as liquid chromatography and mass spectrometry (LC-MS).
This project will develop LC-MS based methods to measure native gut hormones and injected hormone analogues in plasma and target organs such as the brain. AstraZeneca has world leading imaging facilities including mass spectrometry imaging, mass cytometry as well as spatial transcriptomics capabilities.
The combined spatial multi-omics and LC-MS techniques will be used to characterise peptides secreted from a transgenic mouse model producing an engineered biotin ligase enzyme targeted to the endoplasmic reticulum of intestinal epithelium cells. Biotinylated peptides and proteins that are secreted from the murine intestine will be characterised, and their penetration of, and receptor binding in target organs will be investigated.
Project aims
This project will develop LC-MS based methods to measure native gut hormones and injected hormone analogues in plasma and target organs such as the brain.
Contact details
Richard Kay - rgk27@cam.ac.uk
Opportunities
This project is open to applicants who want to do a:
- PhD