The role of aquaporins in spinal cord injury

Swelling of the brain and spinal cord is a devastating consequence of trauma, infection, tumour growth and the obstruction of blood supply. Stroke and traumatic injury are prevalent causes: according to WHO data, 15 million people suffer from stroke worldwide each year (5 million die; another 5 million are permanently disabled) and 60 million people experience a traumatic brain or spinal cord injury leading to disability, long-term health complications or early death. Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults, while brain swelling (oedema) poses a larger global health problem than Alzheimer’s disease. All drugs tested at Phase III clinical trials have failed; treatment is limited to managing symptoms: osmotherapy, administration of diuretics or corticosteroids and surgery to partially remove the skull allowing the brain to swell. There is a clear, unmet and urgent clinical need for an effective oedema therapy.

Aquaporins (AQP) are water channel proteins in glia and astrocytes; controlling the rate of water flow into and out of the central nervous system (CNS). Using AQP knock-out animals, it has been established that the development of acute cytotoxic CNS oedema could be controlled by inhibition of aquaporins (Oshio et al., 2004; Saadoun et al., 2008; Olinski et al., 2014). However, no specific AQP pore-blocking drugs have been identified. Our discovery of the molecular basis of AQP4 regulation provides a translational route to effective therapies that targets a fundamental cellular process: the pharmacological reduction of AQP4 membrane availability. Pore-blocking drugs will affect all AQPs due to their conserved pore structure, but triggers for AQP relocalization are tissue-dependent and unique for each AQP.

In preliminary experiments, we have described a partial mechanism of AQP regulation which provides the rationale for this project. We have identified 2 inhibitors (one experimental and one an FDA-approved drug) that significantly reduce odema after spinal cord injury (SCI). We will therefore evaluate these two drugs in an already validated model of swelling after SCI, by answering the following questions:

1. How effective are AQP4 relocalization inhibitors identified from our in vitro model at reducing oedema in a rat model?

2. What is the complete molecular mechanism of AQP4 regulation, providing us with a framework for drug discovery?

By joining this exciting project you can help to test these hypotheses in experiments involving in vitro and in vivo models of CNS trauma. Your project will take place within Birmingham’s Neuroscience and Ophthalmology Group where you will use cutting edge research facilities covering molecular, cellular and imaging techniques to explore the role of aquaporins in spinal cord injury. You will also benefit from the vibrant interdisciplinary research environment provided by the wider Institute of Inflammation and Ageing groupings, which include scientists focussed on neuroprotection and neuroregeneration after CNS trauma and disease.

Person Specification
Applicants should have a strong background in Neuroscience, biomedical science or biochemistry and ideally a background in molecular neuroscience. They should have a commitment to research in molecular research and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply
Informal enquiries should be directed to Dr Zubair Ahmed ([Email Address Removed])
To apply, please send the following to Dr Zubair Ahmed ([Email Address Removed]):
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.