Kontrolle der ZNS Barrierefunktion durch die Transkriptionsregulatoren Lmo2 und Tal1

大脑的脉管系统具有重要的屏障功能，可以防止免疫细胞的迁移，并控制潜在有害物质从循环中进入。这种血脑屏障需要一个高度专业化的结构，即神经血管单元，它由紧密相关的内皮细胞组成，支持周细胞和星形细胞端足。虽然神经血管单元在健康和患病生物体中的关键作用得到了很好的认识，但其细胞成分之间的相互作用和潜在的分子调控仍然知之甚少。我们的初步数据表明，Notch信号抑制周细胞中有害的、过度收缩的表型，因此对于完整血脑屏障的形成是不可或缺的。在此，我们将结合高分辨率成像和细胞生物学和生物化学实验，采用细胞类型特异性和诱导遗传方法，在小鼠中表征Notch信号通路在中枢神经系统周细胞中的作用。此外，为了深入了解在脑血管系统中介导壁细胞成熟的分子途径，我们将在发育和成年小鼠中使用强大的遗传编码核糖标签分析。这项工作的总结将为Notch和其他信号通路在神经血管相互作用和血脑屏障功能调节中的作用提供重要的见解。

The vasculature of the brain has an important barrier function that prevents the transmigration of immune cells and controls the entry of potentially harmful substances from the circulation. This blood-brain-barrier requires a highly specialized structure, the neurovascular unit, which is composed of tightly associated endothelial cells, supporting pericytes and astrocytic end-feet. While critical roles of the neurovascular unit in the healthy and diseased organism are well appreciated, the interactions between its cellular components and the underlying molecular regulation remain poorly understood. Our preliminary data indicate that Notch signaling suppresses a harmful, hypercontractile phenotype in pericytes and is thereby indispensable for the formation of an intact blood-brain-barrier.Here, we propose to characterize the role of the Notch signaling pathway in pericytes of the central nervous system with cell type-specific and inducible genetic approaches in the mouse, which will be combined with high-resolution imaging and cell biology and biochemistry experiments. In addition, to gain insight into the molecular pathways mediating mural cell maturation in the brain vasculature, we will employ powerful genetically encoded RiboTag profiling in developing and adult mice. The sum of this work will provide important insights into the role of Notch and other signaling pathways in the regulation of neurovascular interactions and blood-brain-barrier function.