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

基本信息

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
项目类别：
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

项目摘要

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 行或更少） HIV 相关神经认知障碍 (HAND) 仍然是美国和全世界近 40 名患者关注的一个问题。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的浸润。大脑中的细胞和病毒复制。这个过程的发生部分是由于血脑屏障（BBB）的丧失完整性，导致渗透性过高和免疫细胞外渗增加。另外，它还不错确定滥用药物可通过增强血脑屏障 (BBB) 功能障碍而加剧 HAND 和神经炎症。控制 BBB 弹性或缺乏弹性以及恢复期间的机制艾滋病毒/药物滥用仍未得到充分研究。该提议基于这样一个中心前提：理解这些机制可以确定加速 BBB 恢复、减弱免疫细胞浸润和最终减缓 HAND 的进展。我们专注于免疫细胞的一个亚类，非经典细胞单核细胞或巡逻单核细胞，已因其在血管中的独特功能而被鉴定维持和体内平衡。巡逻单核细胞已被证明可以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，有助于脉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毒的背景下进行了研究。我们将检验可卡因损害的中心假设巡逻单核细胞功能和 BBB 修复。此外，我们还将研究创新概念脑血管内皮通过细胞外传递血管修复的需要囊泡。我们提出了一种利用体内模型、先进的体外微流体的多边方法 BBB 建模，并分析临床样本以了解巡逻的作用和功能 HIV/药物滥用情况下的单核细胞。重要的是，我们使用先进的体外微流体用原代人类细胞建立血脑屏障模型为研究内皮免疫提供了机会以更接近地模仿人类体内环境的方式进行相互作用。总体而言，研究该提案中包含的内容将推进有关巡逻单核细胞功能、脑内皮-免疫相互作用，并建立滥用药物促进的新机制手。