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

项目总结/摘要 血脑屏障（BBB）破坏通常与许多神经认知障碍相关 并可通过允许有毒和致病物质泄漏到 大脑虽然这种破坏通常与治疗上难以靶向的神经炎症有关， 我们最近在恒河猴中的研究已经导致观察到形态异常的周细胞， BBB破裂的区域。这些表型不同的周细胞，称为2型周细胞（PC 2），已经被 显示随着年龄和感染状态的增加， 表明紧密连接蛋白水平降低和纤维蛋白原外渗增加。我们的研究 表明PC 2可能是减少BBB破坏和维持选择性 磁导率我们假设，BBB支持1型周细胞（PC 1）在BBB期间正在成为PC 2。 在已知调节BBB稳态途径中，PC 2与PC 1具有差异表达 功能在这项研究中，我们建议通过确定是否已知的BBB-2来研究PC 2的分化。 破坏因子可以在体外和体内启动PC 1-到-PC 2的转变。此外，我们将分析 PC 1和PC 2之间的转录组学和蛋白质组学差异，以确定差异调节途径 这可能会影响BBB健康，希望确定潜在的治疗靶点。这些目标的实现 这将提高我们对PC 2如何在体内发育以及为什么PC 2对BBB的支持比 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.