Monocytes, platelets and P2X7R: unravelling the immunological cascade in setting of acute stroke

Research Opportunity
PhD, Masters by Research, Honours, Master of Biomedical Science
Project Status
Future
Department
Medicine and Radiology
Location
Royal Melbourne Hospital
Supervisor Email Number Webpage
Dr Mastura Monif mmonif@unimelb.edu.au
A/Prof Bruce Campbell

Project Details

Ischemic stroke is a major cause of morbidity and mortality in the developed as well developing countries. Immune and inflammatory responses are critical factors in the pathophysiology of acute ischemic damage as well the chronic sequelae. Ischemic stroke is characterized by obliteration of blood flow to a region of the brain as result of a blood clot. The occluding clot / thrombus is generally fibrin and platelet rich in nature. Vessel occlusion and the associated hypoxia inevitably leads to neuronal damage, with associated activation of glial cells, called microglia. Microglia are the immunomodulatory cells of the central nervous system.

Once activated microglia are known to release a myriad of bio-active substances (cytokines and chemokines) locally and into the systemic circulation. These bio-active substances can have short-lived as well long-lasting focal and systemic effects. Also in the ischemic region of the brain, there is infiltration of peripheral macrophages, monocytes and neutrophils. This bidirectional communication between the injured brain and the peripheral immune system can control the progression of stroke pathology as well as tissue repair. Previously we have shown that an ATP sensing receptor, P2X7R is crucial in driving microglial activation in mice. Others have shown that the same receptor is important in release of microparticles from platelets, which can have implications in setting of stroke. Microparticles are small (200-800nm) structures that contain thrombogenic substances as well as cytokines and chemokines.

For this project, we hypothesize that at the time of acute stroke there is increased platelet microparticle release into the circulation and this release is mediated by P2X7R. Also we postulate that monocytes in the periphery at the time of acute stroke have an ‘activated’ phenotype capable of releasing various cytokines / chemokines which can alter the clinical course of the stroke patient. With ethical approval and consent, patients who are having an acute ischemic stroke are recruited into this study. If clinically indicated some patients would undergo clot retrieval (as part of their hospital stroke treatment) where the blood clot that is occluding their artery is retrieved with a catheter.

For this project we will be analysing the cellular composition of the blood clot. In particular we will be focusing on the presence of monocytes/macrophages and expression and function of P2X7R in these cells. In addition we will characterize platelet microparticles at the time of acute stroke versus one month post stroke. We will also gather clinical and radiological data about each patient to correlate with the laboratory findings. Our research would shed light on the cross talk between the peripheral and central immune system at the time of acute stroke. Better understanding of this would help us to devise targeted therapies that can deal with platelet aggregation, monocyte/microglial activation and hopefully preserve neuronal function in the acute and chronic setting.



Faculty Research Themes

Neuroscience

School Research Themes

Neuroscience & Psychiatry



Research Opportunities

PhD, Masters by Research, Honours, Master of Biomedical Science
Graduate Research Students who are interested in joining this project will need to consider their elegibility as well as other Graduate Research requirements before contacting the supervisor of this research

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Key Contact

For further information about this research, please contact a supervisor.

Department

Medicine and Radiology

Research Node

Royal Melbourne Hospital