(MRC DTP) The role of the brain glymphatic system in recovery from cerebral malaria
Dr K Couper
Prof David Brough
Dr Martin Fergie
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
Cerebral malaria is a severe complication of Plasmodium falciparum infection that affects 2 -3 million people, resulting in approximately 300,000 deaths, each year. There is no specific treatment for cerebral malaria other than anti-malarial drugs, and mortality and morbidity associated with cerebral malaria remains unacceptably high (see Riggle et al F1000 Research 2017; 6; 2039). One of the reasons that anti-malarial drug treatment is sub optimal is that the drugs do not directly target the pathological inflammatory pathways that are established within the brain during cerebral malaria. These neuroinflammatory pathways promote and sustain damage to the cerebral blood vessels, cause neuronal dysfunction, and collectively impair brain health (see Strangward et al PNAS 2018 7404-7409). Thus, there is major interest in understanding how neuroinflammation is controlled within the brain following cerebral malaria, to devise new therapies to treat the condition.
In this project the student will focus on the importance of a newly discovered pathway called the glymphatic system in resolving damaging neuroinflammation following anti-malarial drug treatment of cerebral malaria. The glymphatic system is a brain-specialised pathway where cerebrospinal fluid is actively circulated through the brain parenchyma to wash the brain of debris, inflammatory material and catabolites (see recent review by Louveau et al JCI 2017 3210-3219). Dysfunction of the glymphatic system underlies a number of important brain diseases, including Alzheimer’s disease, but the signals that regulate the activity of the glymphatic system are poorly understood.
In this project the student will investigate the role of the glymphatic system in the brain during an experimental model of cerebral malaria, characterising the events that lead to its disruption and then the signals that support its reactivation. Working with established collaborators, the student will then assess whether there is clear evidence that the glymphatic system is disrupted in cases of human cerebral malaria. Overall, the student will characterise how the glymphatic system returns the brain to immunological homeostasis following resolution of cerebral malaria. The outcome of the project will be the identification of new adjunct therapies that can be employed for treatment of cerebral malaria.
The successful candidate will receive training in various cutting edge neuroimmunological techniques including imaging mass cytometry, intravital two photon microscopy, flow cytometry and RNA-sequencing, combined with in vivo training with a number of novel transgenic murine strains. Thus, the successful candidate will obtain essential interdisciplinary and quantitative in vivo skills to support their future career.
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.
This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships
As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.