Identification and characterization of a new pericyte subset: Role in blood-brain barrier breakdown

项目摘要/摘要 血脑屏障(BBB)的破坏通常与许多神经认知障碍有关。 并可通过允许有毒和致病物质泄漏到 大脑。虽然这种干扰通常与治疗上难以靶向的神经炎症有关， 我们最近对恒河猴的研究导致观察到了形态异常的周细胞 血脑屏障崩溃的区域。这些表型不同的周细胞，命名为2型周细胞(PC2)， 随着年龄和感染状况的增加，数量会增加，并与血管有关 表现为紧密连接蛋白水平降低，纤维蛋白原外渗增加。我们的研究 提示PC2可能是减少血脑屏障破坏和维持选择性的有价值的治疗靶点 渗透性。我们假设血脑屏障支持的1型周细胞(PC1)在血脑屏障期间正在变成PC2 PC2与PC1在已知调节血脑屏障内环境平衡途径上有不同的表达 功能。在这项研究中，我们建议通过确定是否已知BBB-来研究PC2的分化 干扰因子可以在体外和体内启动PC1到PC2的转变。此外，我们还将分析 PC1和PC2转录和蛋白质组学差异以确定差异调控途径 这可能会影响血脑屏障的健康，希望确定潜在的治疗靶点。实现这些目标 将提高我们对PC2如何在体内发展以及为什么PC2对血脑屏障的支持程度低于 PC1。

Project Summary/Abstract Blood-brain barrier (BBB) breakdown is commonly noted in association with numerous neurocognitive disorders and can exacerbate persistent neurological issues by allowing the leakage of toxic and pathogenic materials into the brain. While this disruption is often associated with neuroinflammation which therapeutically difficult to target, our recent research in rhesus macaques has led to the observation of morphologically abnormal pericytes in regions of BBB breakdown. These phenotypically distinct pericytes, named type 2 pericytes (PC2), have been shown to increase in number with age and infection status and are specifically associated with vessels demonstrating decreased tight junction protein levels and increased fibrinogen extravasation. Our studies indicate that PC2 may be a valuable therapeutic target to reduce BBB breakdown and maintain selective permeability. We hypothesize that BBB supportive type 1 pericytes (PC1) are becoming PC2 during BBB disruption and that PC2 have differential expression from PC1 in pathways known to regulate BBB homeostatic function. In this study, we propose to investigate the differentiation of PC2 by determining whether known BBB- disrupting factors can initiate a PC1-to-PC2 transition in vitro and in vivo. Additionally, we will analyze the transcriptomic and proteomic differences between PC1 and PC2 to determine differentially regulated pathways that may impact BBB health in the hopes of identifying potential therapeutic targets. The fulfilment of these aims will improve our understanding of how PC2 develop in vivo and why PC2 are less supportive of the BBB than PC1.