Differentiation and characterisation of brain-derived extracellular vesicles from the peripheral blood for understanding the neuropathophysiological mechanisms of migraine.

Migraine is a major disease burden on society but remains poorly understood.

The onset of migraine with aura has been linked to cortical spreading depolarisation (CSD) and Professor Turgay Dalkara (the supervisor) found that inducing CSD in animal models led neurons to release inflammatory proteins in extracellular vesicles (EVs).

Because brain-derived (BD)EVs cross the blood-brain barrier and their composition reflects their cellular and temporal origin, they represent biomarkers that, if isolated from the peripheral blood of migraine patients, could give an unparalleled insight into cell-specific neuroinflammation in migraine.

However, current methods to isolate cell type-specific BDEVs from the blood insufficiently distinguish them from EVs of other tissues, obscuring crucial insights into cell-specific processes.

Here, I (Adam Bennett, the researcher) will develop a workflow to isolate cell type-specific BDEVs from the blood of migraine patients then temporally characterise them to gain a cell-type specific molecular signature during migraine with aura.

This will firstly involve the optimisation and validation of isolating neuron, astrocyte and microglia EVs (using a panel of specific markers) from the brains and peripheral blood of rats.

Secondly, cell type-specific EVs isolated at different time points post-CSD evocation in rats will be characterised using proteomics to generate temporal cell type-specific data on the pathological processes post-CSD.

Thirdly, with optimised time points, cell type-specific EVs will be isolated from the blood of patients after migraine with aura onset and characterised.

In doing so, I will (1) identify previously unknown biomarkers to deepen our understanding of migraine with aura, with possible treatment derivations; (2) create a tool for researchers to investigate other neurological conditions through analysing cell type-specific BDEVs; (3) develop my skillset, publication record, visibility and networks to advance my career.