How is the Blood-Brain Barrier Formed?

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DESCRIPTION (provided by applicant): The signals involved in inducing the blood brain barrier (BBB) during development are poorly understood. Astrocytes, which ensheath capillaries throughout the brain, have been suggested to play a role in the formation of high resistant tight junctions between brain endothelial cells, but this has been surprisingly difficult to demonstrate. It remains possible that other cell types contribute to this function, alone or together with astrocytes. In this proposal, we will try to understand the cellular and molecular interactions that control the development of the BBB. We propose to test whether astrocytes are sufficient to induce this barrier, and to explore the cell-cell interactions between astrocytes, endothelial cells, and other cell types that may induce the BBB. To accomplish these aims, we will utilize the optic nerve as a model system to study BBB development. We will use established techniques to purify and culture endothelial cells, mature astrocytes, and other CNS cells from the developing optic nerve that would interact in vivo affect BBB in vitro. We will try to identify cellular signals that influence optic nerve endothelial cells ability to form high resistance tight junctions, as well as limit their rate of endocytosis. Specifically we will identify signals that induce the expression of tight junction proteins that are specific to the BBB. Understanding whether and how astrocytes control the blood-brain barrier may allow us to develop new ways to deliver drugs into the brain as well as new methods for repairing the barrier after stroke and other neurological conditions.