Role of Patrolling Monocytes in Cerebral Vascular Repair during HIV/Substance Abuse

巡逻单核细胞在 HIV/药物滥用期间脑血管修复中的作用

• 批准号: 10557168
• 负责人: Allison Michelle Andrews
• 金额: $ 14.99万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10557168
• 关键词: Acute; Adoptive Transfer; Affect; Area; Attenuated; Belief; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Cells; Cerebrovascular system; Cerebrum; Chemotaxis; Chronic; Clinical; Cocaine; Cocaine Users; Collaborations; Communication; Cytoskeleton; Data; Drug usage; Endothelium; Environment; Evaluation; Extravasation; Frequencies; HIV; HIV Seropositivity; HIV diagnosis; HIV-associated neurocognitive disorder; Hemorrhage; Homeostasis; Human; Immune; Impairment; In Vitro; Individual; Invaded; Knock-out; Knowledge; Lateral; Macrophage; Maintenance; Mediating; Microfluidics; Modeling; Pathogenesis; Persons; Population; Population Heterogeneity; Prevalence; Process; Proteins; Recovery; Research; Role; Sampling; Scanning; Signal Transduction; Speed; Substance Use Disorder; Substance abuse problem; Surface; Surveys; Testing; Therapeutic; Tight Junctions; Time; United States Department of Veterans Affairs; Universities; Vascular Endothelium; Viremia; Virus Replication; Withdrawal; antiretroviral therapy; blood-brain barrier disruption; blood-brain barrier function; brain endothelial cell; brain parenchyma; cerebrovascular; cocaine exposure; cocaine use; cohort; comorbidity; drug of abuse; extracellular; extracellular vesicles; immune cell infiltrate; in vitro Assay; in vivo; in vivo Model; injured; innovation; intercellular communication; microvesicles; monocyte; neuroAIDS; neuroinflammation; neurovascular unit; novel; preservation; recruit; repaired; resilience; response; restoration; sigma-1 receptor; transcription factor; virtual

Abstract (30 lines or less) HIV-associated neurocognitive disorders (HAND) remain a concern in the US and worldwide for the nearly 40 million people living with HIV. One of the hallmark features of HAND pathogenesis is the infiltration of immune cells and viral replication in the brain. This process occurs in part due to a loss of blood-brain barrier (BBB) integrity, which results in hyperpermeability and increased immune cell extravasation. Additionally, it is well established that drugs of abuse can exacerbate HAND by augmenting blood-brain barrier (BBB) dysfunction and neuroinflammation. The mechanisms that govern BBB resilience, or lack thereof, and recovery during HIV/substance abuse remain understudied. This proposal is based on the central premise that understanding these mechanisms could identify means to speed BBB recovery, attenuate immune cell infiltration and ultimately slow the progression of HAND. We are focused on a subclass of immune cells, non-classical monocytes or patrolling monocytes, that have been identified for their unique functions in vascular maintenance and homeostasis. Patrolling monocytes have been shown to survey the luminal endothelial surface, scavenge debris and initiate vascular repair. These processes are clearly positive effects that aid in the preservation and recovery of the vasculature. However, the functions of these specialized cells have not been studied in the context of substance abuse or HIV. We will test the central hypothesis that cocaine impairs patrolling monocyte function and repair of the BBB. Additionally, we will also investigate the innovative concept that the cerebral vascular endothelium communicates the need for vascular repair through extracellular vesicles. We propose a multilateral approach that utilizes in vivo models, advanced in vitro microfluidic modeling of the BBB, and analysis of clinical samples to understand the role and function of patrolling monocytes in the context of HIV/substance abuse. Importantly, our use of advanced in vitro microfluidic modeling of the BBB with primary human cells presents the opportunity to study endothelial-immune interactions in a way that more closely mimics the human in vivo environment. Overall, the studies encompassed in this proposal will advance current knowledge regarding patrolling monocyte function, cerebral endothelial-immune interactions, and establish a novel mechanism by which drugs of abuse contributes to HAND.

摘要（30行或以下） 艾滋病毒相关的神经认知障碍（HAND）仍然是美国和全球近40年来的一个问题。 100万艾滋病毒感染者。HAND发病机制的标志性特征之一是免疫细胞浸润， 细胞和病毒在大脑中的复制。这一过程的发生部分是由于血脑屏障（BBB）的丧失。 完整性，这导致高渗透性和增加的免疫细胞外渗。另外， 确定滥用药物可通过增加血脑屏障（BBB）功能障碍而加重HAND 和神经炎症。控制BBB弹性或缺乏弹性的机制，以及在 对艾滋病毒/药物滥用的研究仍然不足。这一建议的核心前提是， 这些机制可以确定加速BBB恢复，减弱免疫细胞浸润， 最终导致手的进展缓慢。我们专注于免疫细胞的一个亚类，非经典的 单核细胞或巡逻单核细胞，已被鉴定为它们在血管内皮细胞中的独特功能。 维持和体内平衡。巡逻单核细胞已被证明调查管腔内皮细胞 表面，清除碎片并启动血管修复。这些过程显然是积极的影响， 血管系统的保存和恢复然而，这些特化细胞的功能并没有 在药物滥用或艾滋病的背景下进行了研究。我们将检验可卡因损害 巡逻单核细胞功能和修复血脑屏障。此外，我们还将研究创新概念 脑血管内皮细胞通过细胞外信号传递血管修复的需要 囊泡我们提出了一个多边的方法，利用体内模型，先进的体外微流体 BBB的建模和临床样本的分析，以了解巡逻的作用和功能 单核细胞在HIV/药物滥用的背景下。重要的是，我们使用先进的体外微流体技术， 用原代人细胞模拟血脑屏障为研究内皮免疫功能提供了机会。 以更接近地模拟人类体内环境的方式相互作用。总体而言，研究 本提案所包含的内容将推进有关巡逻单核细胞功能、大脑功能的现有知识 内皮免疫相互作用，并建立一种新的机制，滥用药物有助于 手