09:45 – 10:00 Introduction by the Chair:  Dr. Charlotte Lawson, Royal Veterinary College, UK

10:00 – 10:30 Lymphocyte-mediated endothelial cell signalling pathways modulate blood-brain barrier function Professor Greenwood, UCL, UK
Leukocyte adhesion to brain endothelial cells (BEC) is known to initiate outside-in signalling cascades generated through the engagement of BEC surface adhesion molecules such as ICAM-1. It remains unclear, however, how these individual ICAM-1 mediated signalling modules constitute functional signalling networks or how they perform to support specific functions. Data will be presented that begins to delineate separate signalling pathways that initiate both immediate responses, such as support of leukocyte migration, but also longer term effects on gene regulation that may play a part in the maintenance and resolution of the inflammatory event.

10:30 – 11:00 Rho GTPases as regulators of endothelial cell function Professor Anne Ridley, King’s College London, UKRhoA is a Rho GTPase that regulates actin stress fiber assembly. TNF-? induces stress fibre assembly in endothelial cells, but surprisingly this does not correlate with increased RhoA activity. Leukocytes cross the endothelial barrier either by going between two endothelial cells (paracellular pathway) or by going directly through endothelial cells (transcellular pathway). Our results show that the transcellular pathway requires endothelial caveolae. ICAM-1 is an endothelial leukocyte-binding receptor, and is recruited to caveolae following its engagement, suggesting that it recruits caveolae to form transcellular channels. ICAM-1 also activates RhoA, and we are therefore investigating Rho protein involvement in transendothelial migration.

11:00 – 11:30 Morning Tea/Coffee and Poster Viewing

11:30 – 12:00 Molecular mechanisms of T-lymphocyte migration across the blood-brain barrier – in vitro and in vivo studies Dr Ruth Lyck, University of Berne, Switzerland
In multiple sclerosis and in its animal model experimental autoimmune encephalomyelitis (EAE), inflammatory cells migrate across the blood-brain barrier (BBB) and gain access to the central nervous system (CNS). a4-integrins play a predominant role in leukocyte recruitment across the BBB, whereas the precise contribution of LFA-1 and its endothelial ligands ICAM-1 and ICAM-2 remains to be investigated. Our experimental approaches to delineate the molecular mechanisms involved in the multi-step immune cell recruitment across the BBB will be presented and discussed in the light of therapeutic targeting of ?4-integrin mediated leukocyte migration across the BBB in mutliple sclerosis.

12:00 – 12:30 Monocytes alter blood-brain barrier integrity via reactive oxygen species; implications for neuro-inflammation Dr Elga De Vries, VU Medical Center, Netherlands
Enhanced blood-brain barrier (BBB) permeability and infiltration of inflammatory cells into the brain parenchyma are crucial steps in neuro-inflammation. To enter the central nervous system, leukocytes have to cross the BBB, which consists of specialized brain endothelial cells and their tight junction complexes. We have identified a crucial role for reactive oxygen species (ROS) during the diapedesis of monocytes through changing tight junctions dynamics. Our data indicate that agents that interfere in selective signalling pathways and agents that either reduce oxidative stress or act as anti-oxidants may stabilize the BBB to resist an oxidative attack.

12:30 – 13:00 Group and speakers photo and then*Tour of the BioPark

13:00 – 14:00 Lunch and Poster Viewing

14:00 – 14:30 Determination of the phenotype of human brain endothelium by transcription factors
Professor David Male, The Open University, UK
Brain endothelial cells have a highly specialised phenotype including continuous tight junctions, and transport systems. We have identified transcription factors that are selectively expressed in brain endothelium, in comparison with lung and dermal endothelium. We have then examined how these factors interact with promoters for occludin, claudin-5, pgp1 and the transferrin receptor in order to understand how the phenotype of the endothelium is controlled at the level of transcription.

14:30 – 15:00 Persistent Endothelial Abnormality and Leak at the Blood-Brain Barrier in Multiple Sclerosis, Dr John Kirk, Queen's University Belfast, Ireland
Transient BBB disruption and leak are recognized features of new and recurrent inflammatory lesions in relapsing remitting multiple sclerosis (MS). Using immunofluoresence and confocal laser microscopy on autopsy tissues, our group has shown that the probable primary site of BBB damage in MS is the inter-endothelial tight junction (TJ). We have also compared the extent of TJ abnormality and fibrinogen leak in lesions of different age and activity and in white and grey matter regions in different clinical subtypes. We conclude that Persistent Endothelial Abnormality and Leak (PEAL) is widespread in MS and by its’ compromise of homeostasis may facilitate disease progression.

15:00 – 15:30 Afternoon Tea/Coffee and Last Poster Viewing

15:30 – 16:00 Investigating the utility of momentum-space descriptors for predicting blood-brain barrier penetration, Dr David Cooper,University of Liverpool, UK
It is of course particularly desirable in the development of central nervous system active drugs to know the degree of blood-brain barrier penetration expressed as values of logBB, in which BB is the ratio of the steady-state concentrations of the relevant compound in the brain and in the blood. Given that experimental determination of logBB is not a simple task there has been a great deal of effort to establish QSAR models based on experimentally-determined and experiment-free molecular descriptors. We have demonstrated the potential benefits of incorporating families of momentum-space descriptors, alonside trivial classical descriptors, into QSAR models for predicting logBB values.

16:00 – 16:20 Use of a parallel plate flow chamber to investigate sICAM-1 signalling in endothelial cells.
Miss Sabine Wolf, Royal Veterinary College, UK
Endothelial cells (EC) are continually exposed to hemodynamic forces in the blood vessel. Studies have shown that shear stress induces functional changes in EC. A soluble (s) form of the adhesion molecule ICAM-1 has been found in plasma. Human umbilical vein endothelial cells (HUVEC) were plated out onto slides and mounted onto a parallel flow chamber connected with a recirculating flow loop system (Cytodyne Inc). sICAM-1 is able to bind to activated EC and initiate signalling at arterial flow. This may have clinical relevance in patients with elevated serum levels of sICAM

16:20 Chairman’s summing up & close.