Endothelial calcium signals in the control of neuroinflammation andneurodegeneration

内皮钙信号控制神经炎症和神经变性

• 批准号: 280875586
• 负责人: Professor Dr. Sven G. Meuth
• 金额: --
• 依托单位: Neurologische Klinik
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280875586?language=en
• 关键词: Endothelial; calcium; signals; control; neuroinflammation

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.

血脑屏障(BBB)的深刻改变是神经炎性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细胞的跨内皮迁移方面发挥积极作用。因此，在神经炎性和神经退行性疾病中，内皮细胞往往功能失调。决定免疫细胞允许内皮细胞表型的因素目前还不完全清楚，但涉及离子通道触发的信号转导。此外，精氨酸和色氨酸等氨基酸的分解产物也会导致血脑屏障功能障碍。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，但确切相关的钙信号决定因素尚不清楚。基于自己的进一步的初步数据和已发表的工作，本项目旨在阐明氨基酸代谢产物激活的内皮细胞中的钙信号在神经炎症和神经退变中控制血脑屏障完整性的相关性。为此，将利用遗传和药理学小鼠模型来调节精氨酸和色氨酸分解代谢的不同关键步骤。钙敏感染料和膜片钳分析的使用将能够分析自身免疫性神经炎症和神经变性中氨基酸代谢对内皮细胞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。