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: 10331315
• 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/10331315
• 关键词: Acute; Adoptive Transfer; Affect; Area; Attenuated; Belief; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Cells; Cerebrovascular system; Cerebrum; Chemotaxis; Chemotaxis Inhibition; Chronic; Clinical; Cocaine; Cocaine Users; Collaborations; Data; Drug usage; Endothelium; Environment; Evaluation; Extravasation; Frequencies; Functional disorder; HIV; HIV Seropositivity; HIV diagnosis; HIV-associated neurocognitive disorder; Hemorrhage; Homeostasis; Human; Immune; Impairment; In Vitro; Individual; Infiltration; Knock-out; Knowledge; 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; Tumor-infiltrating immune cells; United States Department of Veterans Affairs; Universities; Vascular Endothelium; Viremia; Virus Replication; Withdrawal; antiretroviral therapy; base; 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; in vitro Assay; in vivo; in vivo Model; injured; innovation; intercellular communication; macrophage; 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(不超过30行) 艾滋病毒相关的神经认知障碍(手)在美国和世界范围内仍然是一个令人担忧的问题，近40 一百万艾滋病毒携带者。手部发病的一个显著特征是免疫细胞的渗透。 细胞和病毒在大脑中的复制。这一过程的部分原因是血脑屏障(BBB)的丧失。 完整性，这会导致高渗透性和免疫细胞外渗增加。另外，它是好的 证实滥用药物可通过增加血脑屏障(BBB)功能而加重手部疾病 和神经炎。管理血脑屏障复原力或缺乏复原力的机制，以及在 艾滋病毒/药物滥用问题仍未得到充分研究。这项提议是基于这样一个中心前提，即理解 这些机制可以确定加速血脑屏障恢复、减弱免疫细胞渗透和 最终减缓手部的进展。我们关注的是免疫细胞的一个子类，非经典的 单核细胞或巡逻单核细胞，已被鉴定为在血管中的独特功能 维持和动态平衡。巡视单核细胞已被证明可以检测管腔内皮细胞 表面，清除碎屑，启动血管修复。这些过程显然是积极的影响，有助于 血管系统的保存和恢复。然而，这些专门细胞的功能并没有 在药物滥用或艾滋病毒的背景下进行了研究。我们将检验可卡因损害的中心假说 巡逻单核细胞功能与血脑屏障的修复。此外，我们还将研究创新的概念 脑血管内皮细胞通过细胞外传递血管修复的需要 水泡。我们提出了一种利用体内模型、先进的体外微流控技术的多边方法 建立血脑屏障模型，并对临床标本进行分析，以了解巡逻的角色和功能 单核细胞在艾滋病毒/药物滥用方面的作用。重要的是，我们使用了先进的体外微流控技术 用原代人类细胞模拟血脑屏障为研究内皮免疫提供了机会 以一种更接近于人体体内环境的方式进行交互。总体而言，这些研究 这份提案中包含的内容将促进当前关于巡逻单核细胞功能、大脑 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。