Work Package 4

Signaling at the neurovascular unit and blood-brain barrier control

Principal Investigator: Professor Martin Lauritzen, Neuronal Signaling Laboratory, Department of Neuroscience and Pharmacology, University of Copenhagen

The work package is divided into five parts all focused on elucidating function and pathology of the neurovascular unit and the blood-brain barrier:

We will develop a method for quantitative determination of BBB permeability using living mice and two-photon microscopy. Currently, most assessment of BBB permeability in animals in vivo is based on isotope methods with one measurement in time in each animal. The goal is to enable us to determine BBB permeability changes in real time at the single capillary level continuously in experimental animals.
We will examine pericyte-astrocyte and astrocyte-pericyte communication with focus on calcium signals in both cell types using genetically engineered mice expressing genetically encoded calcium indicators.
We will develop a stroke model in mice based on middle cerebral artery occlusion. The methods developed in Project 1 will be used to quantify BBB breakdown at the level of single capillaries in the necrotic area, in the penumbra and in the adjacent normal tissue over time.
We will examine whether BBB breakdown in focal ischemia can be ameliorated by blockade of astrocyte and pericyte purinergic receptors, and by inhibitors of MMP9 based on nanoparticle mediated delivery
We will examine diffusion properties of nanoparticles in the brain extracellular space, and the influence of convection and diffusion in the paravascular spaces on the distribution limitations for nanoparticles and macromolecules in brain.