Endothelial calcium signals in the control of neuroinflammation andneurodegeneration

血脑屏障（BBB）的深刻改变是神经炎症和神经退行性疾病的关键和早期事件。内皮细胞是血脑屏障完整性的重要调节者，在限制活化T细胞的跨内皮迁移中发挥积极作用。因此，内皮细胞在神经炎症和神经退行性疾病中通常功能障碍。决定内皮细胞免疫细胞许可表型的因素还不完全清楚，但涉及离子通道触发的信号传导。此外，氨基酸如精氨酸和色氨酸的分解产物有助于BBB功能障碍。虽然这些代谢物激活钙信号并触发内皮细胞的表型和功能变化，但确切的相关钙信号决定因素尚不清楚。基于自己进一步的初步数据和已发表的工作，该项目旨在描绘由氨基酸代谢物激活的内皮细胞中的钙信号在神经炎症和神经变性中控制BBB完整性的相关性。为此，将采用遗传和药理学小鼠模型来调节精氨酸和色氨酸催化剂的不同关键步骤。然后，使用钙敏感染料和膜片钳分析将能够分析在自身免疫性神经炎症和神经变性中通过氨基酸代谢对内皮钙信号的空间和时间控制，以确定潜在的内皮细胞特异性治疗靶点。

A profound alteration of the blood-brain barrier (BBB) is a key and early event in neuroinflammatory and neurodegenerative disorders. Endothelial cells are important regulators of BBB integrity by assuming an active role in limiting transendothelial migration of activated T cells. Consequently, endothelial cells are often dysfunctional in neuroinflammatory and neurodegenerative disorders. The factors which determine the immune cell-permissive phenotype of endothelial cells are only incompletely understood but involve ion channel-triggered signalling. In addition, breakdown products of amino acids such as arginine and tryptophan contribute to BBB dysfunction. While these metabolites activate calcium signals and trigger phenotypic and functional changes in endothelial cells, the exact relevant calcium signal determinants are not known. Based on own further preliminary data and published work, this project aims at delineating the relevance of calcium signals in endothelial cells activated by amino acid metabolites in controlling BBB integrity in neuroinflammation and neurodegeneration. To this aim, genetic and pharmacological mouse models will be employed to modulate different crucial steps of arginine and tryptophan catabolism. The use of calcium-sensitive dyes and patch clamp analyses will then enable the analysis of the spatial and temporal control of endothelial calcium signals by amino acid metabolism in autoimmune neuroinflammation and neurodegeneration in order to define potential endothelial cell-specific therapeutic targets.