How is the Blood-Brain Barrier Formed?

描述(申请人提供)：发育过程中诱导血脑屏障(BBB)的信号知之甚少。星形胶质细胞包裹着整个大脑的毛细血管，被认为在脑内皮细胞之间形成高阻力紧密连接的过程中发挥了作用，但这一点令人惊讶地难以证明。仍然有可能是其他类型的细胞单独或与星形胶质细胞一起参与了这一功能。在这个提案中，我们将试图了解控制血脑屏障发展的细胞和分子相互作用。我们建议测试星形胶质细胞是否足以诱导这种屏障，并探索星形胶质细胞、内皮细胞和其他可能诱导血脑屏障的细胞类型之间的细胞-细胞相互作用。为了实现这些目标，我们将利用视神经作为模型系统来研究血脑屏障的发育。我们将使用成熟的技术来纯化和培养来自发育中的视神经的内皮细胞、成熟星形胶质细胞和其他中枢神经系统细胞，这些细胞在体外会相互作用，影响血脑屏障。我们将尝试识别影响视神经内皮细胞形成高阻力紧密连接的能力的细胞信号，以及限制它们的内吞速率。具体地说，我们将识别诱导BBB特异性紧密连接蛋白表达的信号。了解星形胶质细胞是否以及如何控制血脑屏障可能会让我们开发出将药物输送到大脑的新方法，以及在中风和其他神经疾病后修复血脑屏障的新方法。

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.