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

大脑中的血管需要提供足够的氧气和营养供应，运输激素和其他信号分子，并清除废物。与此同时，脑血管系统阻止潜在有害物质和免疫细胞从循环中进入，从而保护神经元网络的功能。这种血脑屏障涉及内皮细胞、周细胞和星形胶质细胞之间的紧密相互作用，对健康的生物体至关重要，因此，它的破坏是许多人类疾病如中风、神经变性和多发性硬化症的标志。尽管血脑屏障非常重要，但其潜在的分子调控仍然知之甚少。在这里，我们建议使用复杂的小鼠遗传学，RNA测序，染色质修饰分析，细胞共培养实验和功能性体内测定的组合，以解决有关血脑屏障的形成和维护的几个关键问题。特别是，我们的联合研究计划将解决周细胞招募和可塑性的分子原理，通过转运蛋白Mfsd2a调节脑内皮细胞，以及周细胞和内皮细胞之间的相互作用。

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.