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

新周细胞亚群的鉴定和表征：在血脑屏障破坏中的作用

• 批准号: 10318090
• 负责人: Diana Gail Bohannon
• 金额: $ 3万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2023-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318090
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Amyloid; Area; Blood - brain barrier anatomy; Blood Preservation; Brain; Cell Culture Techniques; Cell fusion; Cells; Characteristics; Complement Factor B; Data; Dyes; Extravasation; Fibrinogen; Flow Cytometry; HIV; HIV Infections; HIV tat Protein; HIV-associated neurocognitive disorder; Harvest; Health; Homeostasis; Human; Hypertrophy; Immunofluorescence Microscopy; In Vitro; Infection; Link; Macaca mulatta; Methods; Modeling; Molecular; Morphology; Mus; Names; Neurologic; Neurologic Dysfunctions; Pathogenicity; Pathologic; Pathway interactions; Patients; Pericytes; Permeability; Phenotype; Population; Proprotein Convertase 1; Proteins; Proteomics; Research; Role; Serum Proteins; Severities; Signal Transduction; Smooth Muscle Actin Staining Method; Testing; Therapeutic; Tight Junctions; Toxic effect; Transforming Growth Factors; blood-brain barrier disruption; blood-brain barrier permeabilization; differential expression; efficacy testing; immunocytochemistry; improved; in vivo; in vivo Model; insight; interest; nano-string; nervous system disorder; neurocognitive disorder; neuroinflammation; neurovascular; new therapeutic target; novel; novel therapeutics; prevent; restoration; therapeutic target; transcriptome sequencing; transcriptomics

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.

项目概要/摘要 血脑屏障 (BBB) 破坏通常与多种神经认知障碍有关 并且可以通过允许有毒和致病物质渗漏到体内而加剧持续的神经系统问题 大脑。虽然这种破坏通常与神经炎症有关，而神经炎症在治疗上难以靶向， 我们最近对恒河猴的研究导致观察到形态异常的周细胞 BBB 击穿区域。这些表型不同的周细胞，称为 2 型周细胞 (PC2)，已被 显示数量随着年龄和感染状态而增加，并且与血管特别相关 证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 PC2 可能是减少 BBB 分解和维持选择性的有价值的治疗靶点 渗透性。我们假设 BBB 支持型 1 型周细胞 (PC1) 在 BBB 期间正在转变为 PC2 PC2 与 PC1 在已知调节 BBB 稳态的途径中具有差异表达 功能。在本研究中，我们建议通过确定是否已知 BBB-来研究 PC2 的分化。 干扰因素可以在体外和体内启动 PC1 到 PC2 的转变。此外，我们将分析 PC1 和 PC2 之间的转录组和蛋白质组差异以确定差异调节途径 这可能会影响 BBB 健康，希望找到潜在的治疗靶点。这些目标的实现 将提高我们对 PC2 在体内如何发育以及为什么 PC2 对 BBB 的支持程度低于 PC2 的理解 电脑1。