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.
Blood-brain barrier (BBB) breakdown has been associated with many, if not all, neurocognitive disorders, but previous efforts to explore therapeutic treatments have proven unsuccessful due to a lack of BBB-specific therapeutic target. This project will investigate whether a newly observed pericyte subset which occurs in regions of BBB breakdown may act as a potential therapeutic target by determining unique transcriptomic and proteomic profiles of different pericytes and identifying substances that can trigger pericyte transition. Improving our understanding of this unique pericyte subset could provide novel insight into signaling abnormalities that occur during BBB breakdown and likely provide new therapeutic targets to improve BBB stability.
