Cellular and molecular mechanisms of blood-brain barrier formation and maintenance

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Blood vessels in the brain need to provide adequate oxygen and nutrient supply, transport hormones and other signaling molecules, and remove waste products. At the same time, the brain vasculature prevents the entry of potentially harmful substances and immune cells from the circulation and thereby protects the functionality of neuronal networks. This blood-brain barrier, which involves tight interactions between endothelial cells, pericytes and astrocytes, is critical for the healthy organism and, accordingly, its breakdown is a hallmark of numerous human diseases such as stroke, neurodegeneration and multiple sclerosis. Despite of the great importance of the blood-brain barrier, the underlying molecular regulation remains little understood. Here, we propose to use a combination of sophisticated mouse genetics, RNA sequencing, analysis of chromatin modifications, cell co-culture experiments, and functional in vivo assays to resolve several key questions regarding blood-brain barrier formation and maintenance. In particular, our joint research program will address molecular principles of pericyte recruitment and plasticity, the regulation of the brain endothelium by the transporter Mfsd2a, and the interplay between pericytes and endothelial cells.