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，在德国每年因疾病造成的经济损失高达60亿欧元。由于对这种疾病的病理生理学和再生机制只有部分了解，目前还没有治疗缺血性损伤后果的对症疗法。在这种背景下，尽管Eph/EPhin受体/配体系统决定了大脑的起源、结构和功能，但它的作用迄今尚未被研究过。我们在小鼠中风模型上的初步工作表明，在脑缺血后过程中，膜相关配体ePhinB1和ewitinB2以及受体EphB2和EphB4对于血管内皮细胞和免疫细胞的促炎激活和导航至关重要。因此，这项建议应该研究在这种情况下EphB/ewitinB-系统如何调节内皮细胞和免疫细胞的功能。因此，工作计划特别侧重于以下方面的分析：(I)与脑水肿形成和白细胞(单核细胞、粒细胞)迁移有关的血脑屏障功能的相关性；(Ii)与缺血相关的白细胞和常驻免疫细胞(小胶质细胞、星形胶质细胞)由EphB/ePhinB系统激活。

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.