Impact of the EphB/ephrinB system on inflammation and edema formation during cerebral ischemia

中风是西方世界最相关的死亡原因之一，每年在德国造成60亿欧元的疾病经济损失。由于这种疾病的病理生理学和再生机制仅被部分理解，因此没有针对缺血性损伤后果的病因治疗。在这种情况下，Eph/肝配蛋白受体/配体系统的作用至今尚未研究，尽管它决定性地控制着大脑的发生、结构和功能。我们对小鼠中风模型的初步研究表明，膜相关配体ephrinB 1和ephrinB 2以及受体EphB 2和EphB 4对于脑缺血后过程中内皮细胞和免疫细胞的促炎激活和导航至关重要。因此，本建议应该调查EphB/ephrinB系统如何调节内皮细胞和免疫细胞在这些情况下的功能。因此，该工作计划具体集中于分析（i）ephrinB 1/B2与血脑屏障功能的相关性，所述血脑屏障功能与脑水肿的形成以及白细胞（单核细胞、粒细胞）的迁移有关，以及（ii）EphB/ephrinB系统对白细胞和驻留免疫细胞（小胶质细胞、星形胶质细胞）的缺血相关激活。

Stroke is one of the most relevant causes of death in the western world and responsible for 6 billion euro economic costs caused by illness in Germany annually. As the pathophysiological and regenerative mechanisms of this disease are only partially understood, no causative therapy dealing with the consequences of the ischemic insult is available. In this context, the role of the Eph/ephrin-receptor/ligand-system has not been investigated so far although it decisively controls genesis, architecture and function of the brain. Our preliminary work on a mouse stroke model indicates that the membrane-associated ligands ephrinB1 and ephrinB2 as well as the receptors EphB2 and EphB4 are crucial for the pro-inflammatory activation and navigation of endothelial and immune cells in the context of post-ischemic processes in the brain. Thus, this proposal is ought to investigate as to how the EphB/ephrinB-system regulates the function of endothelial and immune cells under these circumstances. Consequently, the working program is specifically focused on the analysis of (i) the relevance of ephrinB1/B2 for the function of the blood-brain-barrier with respect to the formation of brain edema as well as the transmigration of leukocytes (monocytes, granulocytes) and (ii) the ischemia-related activation of leukocytes and resident immune cells (microglia, astroglia) by the EphB/ephrinB-system.