Kinase inhibitor modulation of endothelial barrier properties

Breakdown of the blood-brain barrier (BBB) is associated with brain swelling, which is life-threatening in diseases like cerebral malaria. However, there are currently limited strategies to stabilize the BBB in the context of inflammation. In pediatric cerebral malaria, both parasite and host stimuli, such as elevated levels of thrombin, an essential clotting factor, are implicated in endothelial dysfunction. To identify candidate drugs that target disease processes and to deepen our understanding of endothelial barrier regulation, we have used a kinase regression approach. Kinase regression exploits the polypharmacology of kinase inhibitors and machine learning to investigate kinase signaling pathways that regulate a specific phenotype. In this study, we used the xCelligenceTM system to monitor permeability of human brain endothelial cell monolayers in real time in response to 28 kinase inhibitors. This led to the identification of a subset of kinase inhibitors that protect against thrombin-induced permeability. Notably, kinase inhibitors that strengthened the barrier under resting conditions also protected against thrombin-induced barrier disruption, suggesting that common pathways may enhance barrier properties and protect against barrier-disruption. Our data were used to train a machine learning model that predicted 50 kinases to be important in regulating the endothelial barrier. In this talk, we will present our experimental approach and findings, and demonstrate that kinase inhibitors may be a viable strategy to pursue for cerebral malaria adjunctive therapy.