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 细胞外囊泡（EV）在神经元存活和中枢免疫监视中发挥重要作用 神经系统（CNS）通过介导神经元和其他脑细胞之间的细胞间通讯。 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 最近，我们证明了细胞内和循环的 HIV 限制性 microRNA (miRNA) 的数量。 EVs可以将抗病毒信号从免疫激活的脑微血管内皮细胞（BMVEC）传递到 巨噬细胞，导致 HIV 抑制 此外，我们还发现来自 HIV 感染者的血浆 EV。 富集了几种具有神经毒性作用（miR-21和let-7）或靶向紧密连接蛋白（miR-17和 miR-20a）因此我们得出阿片类药物和/或 HIV 会损害血脑屏障（BBB）的完整性并发挥作用。 我们提出了两个具体目标来解决 EV 介导的 miRNA 细胞间传输的神经毒性。 该假设： 具体目标 1. 确定 EV 介导的 miRNA 对 BBB 先天免疫的影响 使用阿片类药物时的 HIV 和神经元损伤；具体目标 2. 从机制上研究 BMVEC 的作用 和血浆衍生的 EV 在 BBB 先天抗病毒免疫和神经损伤中的作用，我们将产生生物工程 然后，我们将确定这些 miRNA 的 3' UTR 靶点以及是否包含特定 miRNA 的外泌体。 这些 miRNA 参与 BMVEC 和神经元细胞中免疫激活和炎症的调节。 该项目的研究结果将为 EV 介导的 BBB 对 HIV 和病毒的先天免疫提供科学证据。 阿片类药物和/或艾滋病毒介导的神经元损伤的新机制。