Opioids, Extracellular Vesicles and BBB Innate Immunity

阿片类药物、细胞外囊泡和 BBB 先天免疫

• 批准号: 9381158
• 负责人: WENZHE HO
• 金额: $ 23.78万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381158
• 关键词: 3' Untranslated Regions; Address; Adhesions; Algorithms; Antiviral Agents; Biomedical Engineering; Blood - brain barrier anatomy; CCL2 gene; CCR5 gene; Cells; Data; Engineering; Enzyme-Linked Immunosorbent Assay; HIV; HIV Infections; Heroin; Heroin Users; Immune signaling; Immunity; Immunologic Surveillance; Impairment; In Vitro; Infection; Inflammation; Inflammatory Response; Injecting drug user; Intercellular adhesion molecule 1; Mediating; MicroRNAs; Morphine; Natural Immunity; Neuraxis; Neuronal Injury; Neurons; Opiates; Opioid; Plasma; Play; Predisposition; Proteins; RNA; Research; Role; Small RNA; Source; System; Tight Junctions; United States; Validation; Vascular Cell Adhesion Molecule-1; Viral; Viral Physiology; antiviral immunity; brain cell; brain endothelial cell; cofactor; exosome; extracellular vesicles; immune activation; immunoregulation; in vivo; injection drug use; intercellular communication; macrophage; microRNA biomarkers; migration; monocyte; neuronal survival; neurotoxic; neurotoxicity; novel; opioid use; sensor; transcriptome sequencing; transmission process

Abstract Extracellular vesicles (EVs) play an important role in neuronal survival and immune surveillance of the central nervous system (CNS) by mediating the intercellular communication between neurons and other brain cells. Our early in vitro and in vivo studies showed that opioids (morphine and heroin) and/or HIV could inhibit the expression of a number of the intracellular and circulating HIV restriction microRNAs (miRNAs). Recently, we demonstrated that EVs could shuttle antiviral signals from immune-activated brain microvascular endothelial cells (BMVEC) to macrophages, resulting in HIV inhibition. In addition, we showed that plasma EVs from HIV-infected subjects enriched several miRNAs that have neurotoxic effect (miR-21 and let-7) or target tight junction proteins (miR-17 and miR-20a). We thus hypothesize that opioids and/or HIV impair the blood-brain barrier (BBB) integrity and exert neurotoxicity via EVs-mediated intercellular transmission of miRNAs. We propose two specific aims to address this hypothesis: Specific Aim 1. To determine the impact of EVs-mediated miRNAs on BBB innate immunity against HIV and neuronal injury in the context of opioid use; Specific Aim 2. To mechanistically study the role of BMVEC- and plasma-derived EVs in the BBB innate antiviral immunity and neuronal injury, we will generate bioengineered exosomes that contain the specific miRNAs. We will then determine the 3’ UTR targets of these miRNAs and whether these miRNAs are involved in the modulation of immune activation and inflammation in BMVEC and neuronal cells. The findings from this project will provide scientific evidence of EVs-mediated BBB innate immunity against HIV and a novel mechanism for opioid and/or HIV-mediated neuronal injury.

抽象的 细胞外蔬菜（EV）在中央的神经元存活和免疫监测中起重要作用 神经系统（CNS）通过介导神经元与其他脑细胞之间的细胞间通信。我们的早期 体外和体内研究表明，阿片类药物（吗啡和海洛因）和/或HIV可以抑制A的表达 细胞内和循环的HIV限制microRNA（miRNA）的数量。最近，我们证明了 电动汽车可以从免疫激活的脑微血管内皮细胞（BMVEC）从免疫激活的抗病毒信号穿上抗病毒信号至 巨噬细胞，导致HIV抑制。此外，我们证明了来自HIV感染受试者的血浆EV 富集具有神经毒性作用（miR-21和Let-7）或靶向紧密连接蛋白（miR-17和MiR-17和 mir-20a）。因此，我们假设阿片类药物和/或HIV损害了血脑屏障（BBB）的完整性和运动 通过电动汽车介导的miRNA的细胞间传播神经毒性。我们提出了两个特定的目的来解决 该假设：具体目的1。确定电动汽车介导的miRNA对BBB先天免疫的影响 在使用阿片类药物的情况下，艾滋病毒和神经元损伤；具体目标2。机械地研究BMVEC-的作用 BBB先天抗病毒免疫学和神经元损伤中的血浆衍生的电动汽车，我们将产生生物工程 包含特定miRNA的外泌体。然后，我们将确定这些miRNA的3’UTR目标以及是否 这些miRNA参与了BMVEC和神经元细胞中免疫激活和炎症的调节。 该项目的发现将提供电动汽车介导的BBB先天免疫对艾滋病毒和艾滋病毒的科学证据 阿片类药物和/或HIV介导的神经元损伤的新型机制。