Rob Krams
Chair in Molecular Bioengineering
Department of Bioengineering
Imperial College London
United Kingdom
thursday, august 18th
11:00 a.m.
room 1128 • ibb
Atherosclerotic plaques are non-uniformly distributed over the arterial system and ample evidence point to a role of blood flow in the formation of these atherosclerotic predilection sites. Blood flow exerts its effect on the vessel wall through mechanical activation of ~ 7 endothelial
signalling pathways and 8 acknowledged transcription factors, controlling ~ 2000 endothelial genes. As a consequence, endothelial cells express adhesion factors, change their permeability to lipids and produce diffusible factors under the influence of blood flow which affect the signalling in and composition of the vascular wall.
In our group, signalling networks in the endothelial cell are studied with commercially available(microarrays/rapid sequencer) and custom-designed high throughput analysis methods (siRNA platform; top-down method) and by studying small signalling modules (bottom-up method). The screens from microarrays and rapid sequencers are analysed with methods to infer signalling networks and a new siRNA platform is developed for a systematic analysis of these networks to rapidly and systematically validate these networks. In parallel to this approach, small signalling
modules are simulated and experimentally tested in flow chambers with the aim to build larger
networks. We will discuss two signalling networks: the IKK-NF-κB pathway and the MAPK5-KLF-pathways in relation to their regulation of the eNOS-NO pathway.
Blood flow also exerts effect on plaque growth and plaque composition with a currently unknownmechanism. We will provide data for a cellular-chemokine biological network induced by low shear stress that plays in important role in vulnerable plaque formation. We will present ongoing studies aimed at extending this idea and using it as a tool for molecular imaging.
Finally, we aim to bring these two lines of research together where the mechaonsensitive signalling pathways of endothelial cells are studied and targeted for prevention of plaque formation.