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Dissecting the molecular basis for malaria-linked blood vessel pathology in the brain and retina

   School of Medicine, Dentistry & Biomedical Sciences

  Prof A Stitt, Prof R Medina  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Cerebral malaria (CM) remains a major cause of morbidity and death. Plasmodium falciparum infected red blood cells cause disruption of the blood-brain/retina barrier, haemorrhage and localised thrombosis in the CNS. This project will examine the molecular dynamics of several inter-linked receptor systems, ultimately to protect against malaria-mediated vasculopathy.

Cerebral malaria (CM) remains a major cause of morbidity and death and is caused by the sequestration of Plasmodium falciparum– infected red blood cells (Pf-iRBCs) in the capillaries of the brain. This causes disruption of the blood-brain barrier (BBB), vascular haemorrhage and localised thrombosis. Comparable vascular pathology and compromise of the blood-retinal barrier (BRB) occurs in malaria retinopathy (MR), which suggests that the CNS vasculature reacts similarly to Pf-iRBCs. The endothelial protein C receptor (EPCR) - angiotensin II (Ang II) axis modulates engagement of the malaria parasite with the CNS vasculature. There is a need to further understand this pathway and this project will test the hypothesis that activation of the Ang II type 2 receptor (AT2) in EPCR-expressing endothelial cells in the retina and brain can be protected from malaria-related oedema, haemorrhages and loss of brain and retinal function. The objectives of this project are: 1) To determine differential responses of brain and retinal vascular endothelium exposed to Pf-iRBC using 10x Genomics single-cell RNA-seq (scRNA-seq) analysis 2) To understand the mechanism of protection of endothelial integrity in an in vitro model of CM 3) To establish the role of EPCR for CNS endothelium infection and protection by AT2 agonism using in vitro and in vivo models 

Start Date: October 2022

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