Mechanisms of endothelial dysfunction in cerebral malaria and barrier restorative pathways

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Project Abstract Endothelial activation, dysfunction, and barrier disruption are hallmarks of inflammation-related diseases, such as malaria, sepsis, and viral hemorrhagic fever. Cerebral malaria is a severe complication of infection with Plasmodium falciparum malaria parasites. In patients with cerebral malaria, red blood cells infected with malaria parasites bind within cerebral microvessels leading to microvascular obstruction, thrombosis, breakdown of the blood-brain barrier (BBB), and severe brain swelling. The molecular mechanisms of how the complex parasite and host inflammatory stimuli cause breakdown of the blood-brain barrier are only partially understood, and strategies to restore BBB integrity remain limited. Kinase inhibitors are potential drugs to stabilize the endothelial barrier following hyperinflammatory damage. This project builds on our recent findings that specific kinase inhibitors promote endothelial barrier strengthening and protect against thrombin-induced barrier disruption. In this project, we will investigate the mechanism(s) of action of barrier-protective kinase inhibitors using in vitro human brain endothelial cell models and study how endothelial cells integrate signals from host and parasite inflammatory products. Using a new 3D human brain microvessel model, we will also study how flow disturbances interact with host and parasite stimuli in endothelial activation and barrier disruption. Finally, we will evaluate the efficacy of barrier-protective kinase inhibitors using a combination of the in vitro 3D human brain microvessel model and an experimental cerebral malaria (ECM) mouse model. The proposed studies will study kinase regulation of endothelial barrier integrity and investigate the potential of kinase inhibitors to stabilize endothelial barrier properties, with the long-term goal of developing new therapeutic approaches to treat a wide spectrum of clinical disease associated with endothelial dysfunction.