(MRC DTP) Understanding the role of platelets in stroke through comprehensive immunological assessment in relevant clinical cohorts and preclinical models

Stroke affects approximately 100, 000 people each year in the UK, and remains the leading cause of adult disability (1). The majority of strokes are associated with arterial occlusion (ischaemic stroke: 85%), whilst the remainder are due to haemorrhage into the brain or subarachnoid spaces (haemorrhagic stroke: 15%). Unfortunately, treatment options for ischaemic or haemorrhagic stroke are limited posing a major unmet need for research and clinical practice.

It is widely recognised that dysregulated inflammation and thrombosis are strongly implicated in the pathophysiology of stroke disease, both in terms of risk of stroke, and evolution of injury and repair of tissue injury. Further, transient suppression of innate cellular immune responses increases susceptibility to infections after stroke, which occur commonly and adversely impact upon outcomes. Thrombo-inflammatory-immune pathways therefore play a critical part in determining outcomes from stroke and provide opportunities for therapeutic intervention.

Platelets are myeloid-derived blood cells which circulate in the blood with a lifespan of 7-10 days. Although they lack a nucleus, they are increasingly recognised as complex cells and contain 3 discreet types of granules (α-granules, dense granules and lysosomes) and residual RNA. Whilst the role of platelets as the primary mediators of thrombosis-haemostasis is long established, they are also increasingly emerging as key mediators of innate immune responses (2). Platelets directly interact with leucocytes (e.g. monocytes, neutrophils and dendritic cells) via specific surface receptors, forming platelet-leucocyte complexes which influence both innate and adaptive immune responses. Further, platelets can also bind bacteria commonly implicated in stroke-associated infections, and release antimicrobial products which may supplement other innate cellular defence mechanisms. Despite the increasing recognition of platelets in immune responses, the precise functional and clinical relevance of platelet-immune cellular interactions in stroke are poorly characterised or understood.

We have recently established comprehensive protocols for mapping immunophenotype and functional status of peripheral blood innate (monocyte, neutrophil) and adaptive (lymphocyte) cellular components and applied these successfully to blood samples from rodents with experimental stroke and patients with stroke. The overall aim of this project is to develop complementary methodologies to evaluate platelets in cerebrovascular disease. The objectives are to establish reproducible protocols for isolating platelets from whole blood samples and for evaluating immunophenotype, leucocyte-binding and functional status. These methods will be applied to blood samples from rodent models of experimental stroke, healthy human controls and patients with acute ischaemic and haemorrhagic stroke.

https://www.research.manchester.ac.uk/portal/john.grainger-2.html
https://www.research.manchester.ac.uk/portal/stuart.allan.html
https://www.research.manchester.ac.uk/portal/craig.smith-2.html

Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.