Kontrolle der ZNS Barrierefunktion durch die Transkriptionsregulatoren Lmo2 und Tal1

转录调节因子 Lmo2 和 Tal1 对 CNS 屏障功能的控制

• 批准号: 289319247
• 负责人: Professor Dr. Ralf H. Adams
• 金额: --
• 依托单位: Max-Planck-Institut für molekulare Biomedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/289319247?language=en
• 关键词: Kontrolle; der; ZNS; Barrierefunktion; durch

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.

大脑的脉管系统具有重要的屏障功能，可防止免疫细胞的迁移并控制潜在的有害物质从循环中进入。这种血脑屏障需要一个高度专业的结构，即神经血管单元，该结构由紧密相关的内皮细胞组成，支撑周细胞和星形胶质细胞末端。虽然神经血管单位在健康和患病生物体中的关键作用得到了很好的认识，但其细胞成分与潜在的分子调节之间的相互作用仍然鲜为人知。 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生物学和生物化学实验。此外，为了深入了解介导脑脉管系统中壁细胞成熟的分子途径，我们将在发育和成年小鼠中采用强大的遗传编码的核果分析。这项工作的总和将为Notch和其他信号通路在调节神经血管相互作用和血脑屏障功能方面的作用提供重要见解。