? Solute distribution between blood and brain is strictly regulated by the blood-brain barrier (BBB) at brain capillary endothelial cells. While the BBB performs an important function in keeping unnecessary or harmful molecules from the brain, it poses a challenging problem in delivering therapeutics, including anticancer, antibiotic or antipsychotic drugs into the brain. Conversely, preventing potentially damaging molecules from overcoming the BBB is also an increasing problem, especially when combinations of xenobiotics are encountered. Medical and pharmaceutical scientists therefore have a growing need for rapid, reliable in vitro models of the human BBB for preclinical safety and efficacy screening. To fulfill this unmet need, an in vitro BBB model based on human endothelial cells will be developed. Human endothelial cells will be co-cultured with human astrocytes on a microporous membrane coated with extracellular matrix material in defined serum-free medium to produce a tight monolayer of endothelial cells possessing BBB properties. The model will be characterized in Phase I with respect to important attributes of the BBB function including formation of functional tight junctions and expression of functional efflux transporters. Further characterization and validation will proceed during Phase Il, and the model will be used to study strategies for modulation of BBB function. ? ? ?
