Our chief interest is the ‘multi-tasking’ blood-brain barrier (BBB). The brain capillary endothelium forming the BBB regulates molecular traffic between blood and brain, and protects the brain from potentially harmful substances circulating in the blood. Understanding the complexity of BBB physiology helps in the design of modern CNS drug therapies. Many neuropathologies involve BBB breakdown or dysfunction – treating the barrier could help reduce the severity of neurodegeneration and aid repair.

Developing good in vitro models of the BBB
We have optimised several cell culture models of the brain endothelium that permit study of a range of functional activities of the BBB, and may have applications in screening drugs for permeability across the BBB.

Transport functions of the BBB and flow of interstitial fluid
The BBB has uptake and efflux carriers mediating bi-directional molecular transport. We are examining transporters that could be used to deliver drugs to the brain, and others (efflux transporters) that impede drug entry. We are also studying BBB ion transport, and its key role in the formation and regulation of brain interstitial fluid (ISF). We are mapping the routes for ISF flow, with application in programmes designed to deliver therapeutic agents to the brain. Disturbances of ISF production and flow may be involved in several brain disorders including stroke and tumours.

Cell:cell signalling at the BBB
The ‘BBB phenotype’ develops in brain endothelium under the inductive influence of closely associated cell types, especially astrocytic glial cells. The mature BBB appears to be modulated physiologically by signals from glia and neurons, and possibly other cell types, allowing coordination of the ‘neurovascular unit’. We are using cell culture models and fluorescence imaging to determine the receptors present, and their role in cell:cell signalling. Many of the endothelial receptors we have identified cause a rise in intracellular calcium – a possible first step in signal transduction pathways by which glial cells (and neurons) could influence endothelial physiology (tightness, transport function, metabolism).

BBB modulation in pathology
We have a number of collaborative projects on the role of BBB dysfunction in neurological disorders, including multiple sclerosis. The aim is to understand the mechanisms by which the barrier may be impaired, and the implications for the neurological condition. We are also exploring therapeutic strategies that may reduce BBB damage and hence limit the severity of brain disorders.

Drug delivery across the BBB
By careful examination of the routes for molecular movement across the BBB we are developing ‘predictive rules’ to guide the design of drug compounds to target or avoid the brain. So far this works best for lipid soluble compounds passively diffusing across the endothelial lipid membranes. The next step will be to incorporate understanding of uptake and efflux transporter function. We are also working on novel methods for delivering ‘problem drugs’ (large or polar molecules) including use of nanoparticle delivery systems, and transient opening of the BBB. Our successful ‘BBB Consortium with Industry’ is now operating in ‘Club’ mode: organising meetings, advising on new developments, and setting up joint research projects (enquiries welcome)