Endothelial calcium signals in the control of neuroinflammation andneurodegeneration

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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.