The functional, metabolic and molecular cortisol-induced reprogramming of platelets.

Platelets are blood cells which circulate the body continually probing for damage to the vessel wall. On recognition of damage, platelets rapidly become activated and recruit additional platelets and immune cells to the site of injury, this function supports stable haemostasis. Aberrant platelet activation occurs in many diseases and leads to thrombotic events, which drive myocardial infarction and stroke. Platelet dysfunction is typically underpinned by underlying platelet hyperactivity. There are observational studies which describe that many thrombotic platelet events occur in the morning and that this correlates with endogenous cortisol production. Cortisol is regulated by the hypothalamus-pituitary-adrenal axis and follows the circadian cycle with a peak in mid-morning and nadir in the early hours, with this peak correlating with increased platelet activity.

This project seeks to characterise the cortisol and platelet relationship, demonstrating that platelet function is linked to the temporal production of endogenous cortisol. To this end, the study will explore the cortisol-platelet axis at a molecular, metabolic and functional level. This will include functional platelet assays utilising flow cytometry, metabolic profiling utilising bioenergetics, and molecular profiling with a range of signalling and pathway-inhibitors to identify key signalling nodes in the cortisol-platelet axis. This research will be performed using primary samples from healthy donors taken at different time-points throughout the day thereby assessing platelets a different tonic levels of endogenous cortisol production. In vitro use of cortisol-stimulated naïve samples will be used to validate ex vivo findings.

You will develop key skills throughout this PhD including a wide range of laboratory, data processing, and presentation skills. This study will address the important and currently poorly understood mechanisms of the cortisol-platelet axis and will lead to novel findings, and opportunities for publications, conference proceedings and outreach.