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

School of Medicine, Dentistry and Biomedical Sciences | PHD
Funding
Unfunded
Reference Number
SMED-2221-1181
Application Deadline
None specified
Start Date
None specified

Overview

Cerebral malaria (CM) remains a major cause of morbidity and death. Plasmodiumfalciparuminfected red blood cells causedisruption ofthe blood-brain/retinabarrier, haemorrhage and localised thrombosisin 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 deathand is caused bythe sequestration of Plasmodiumfalciparum–infected red blood cells(Pf-iRBCs)in the capillaries of the brain. Thiscauses disruption ofthe 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. Theendothelial 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 cellsin the retina and brain can be protected from malaria-relatedoedema, haemorrhages and loss of brain and retinal function.The objectives of this project are:1)To determinedifferentialresponses of brain and retinal vascular endothelium exposed to Pf-iRBCusing 10xGenomics single-cell RNA-seq (scRNA-seq) analysis2)To understandthe mechanism of protection of endothelial integrity in an in vitromodel of CM
3)Toestablishthe role of EPCR for CNS endothelium infection and protection by AT2 agonismusing in vitro and in vivo models

Project Summary
Supervisor

Prof Alan Stitt

Research Profile


Mode of Study

Full-time: 3 Years


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