This sandwich placement will be based in the Metabolomics STP supervised by James MacRae.

Project summary

This project centres on the development of analytical tools for the investigation of metabolic activation by an important class of cholesterol-derived lipids – the oxysterols.

Oxysterols have a broad spectrum of physiological influence, including bile acid and steroid hormone synthesis, pro-inflammatory signalling, cellular differentiation, and others. While we are particularly interested in understanding their role in pregnancy, oxysterols have also been implicated in many diseases, including cardiovascular disease, neurological diseases, and cancer.

Despite this, oxysterol analysis remains challenging. Using state-of-the-art high resolution mass spectrometry instruments and building on in-house lipidomics methods [1], this project will focus on developing new, sensitive methods to detect, measure, and identify oxysterols.

Working with the Charalambous lab, we will explore the molecular mechanisms by which oxysterols and the placenta drive maternal metabolic adaptations critical to pregnancy.

During pregnancy, the mother must provide adequate nutrients to the foetus for optimal growth and organogenesis. Consequently, coordination of metabolism is a key adaptation in pregnancy. This metabolic coordination was recently shown to be controlled by the activation of a master regulator of lipid metabolism - the ‘liver-X receptor (LXR)’ pathway - in the maternal liver, promoting transport of fatty acids to the developing foetus [2].

The LXR pathway itself is activated by cholesterol derivatives – most notably, oxysterols. Interestingly, metabolic targets of LXR are activated after development of the placenta, suggesting that the oxysterols responsible for LXR activation may have a placental origin.

We will use the methods developed in this study to discover and describe the role of oxysterols generated within placental cells and subsequently released into the circulation. These techniques will also provide a valuable new tool for investigation of the roles of oxysterols across human physiology.

This project is most suited to those interested in developing analytical chemistry skills, and using these to address biological questions.

Candidate background