How is the Blood-Brain Barrier Formed?

描述（由申请人提供）：对发育期间诱导血脑屏障（BBB）的信号了解甚少。星形胶质细胞包裹整个大脑的毛细血管，已经被认为在脑内皮细胞之间的高抗性紧密连接的形成中发挥作用，但这令人惊讶地难以证明。其他细胞类型单独或与星形胶质细胞一起有助于这一功能。在这个建议中，我们将试图了解控制BBB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，内皮细胞和其他细胞类型，可能会诱导血脑屏障之间的细胞-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BBB的发展。我们将使用已建立的技术纯化和培养内皮细胞，成熟的星形胶质细胞，和其他中枢神经系统细胞从发展中的视神经，将在体内相互作用，影响血脑屏障体外。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，我们将确定信号，诱导表达的紧密连接蛋白是特定的血脑屏障。了解星形胶质细胞是否以及如何控制血脑屏障可能使我们能够开发新的方法将药物输送到大脑中，以及在中风和其他神经系统疾病后修复屏障的新方法。

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.