Exosomes in tobacco-and HIV-mediated neurotoxcity

烟草和艾滋病毒介导的神经毒性中的外泌体

• 批准号: 9174185
• 负责人: Santosh Kumar
• 金额: $ 24.1万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174185
• 关键词: Accounting; Apoptotic; Asses; Benzo(a)pyrene; Biological Markers; Biology; Cells; Data; Exposure to; Future; Goals; HIV; HIV Infections; HIV therapy; HIV-associated neurocognitive disorder; Hepatitis C; Human Papillomavirus; In Vitro; Incentives; Individual; Knowledge; Link; Measures; Mediating; Mediator of activation protein; Microglia; Neurons; Outcome; Oxidative Stress; Oxidative Stress Pathway; Pathogenesis; Pathway interactions; Plasma; Play; Population; Proteins; Research; Role; Sampling; Small Interfering RNA; Smoker; Smoking; Substance abuse problem; Testing; Tobacco; Tobacco smoking; U937 Cells; Virus; Virus Diseases; Work; antioxidant enzyme; brain cell; cancer therapy; cigarette smoking; drug of abuse; environmental tobacco smoke exposure; exosome; extracellular vesicles; in vivo; inhibitor/antagonist; innovation; macrophage; monocyte; neurotoxicity; novel; overexpression; physical property

Tobacco smoking is highly prevalent in the HIV-infected population, and is known to exacerbate HIV pathogenesis. HIV infection to the brain cells such as microglia and macrophages are known to cause HIV- associated neurocognitive disorder (HAND) in 50% of the HIV+ population. Since tobacco constituents, mainly benzo(a)pyrene (BaP), also cause neurotoxicity, together they may further exacerbate neurotoxicity in HIV- infected smokers. Extracellular vesicles, especially exosomes (30-100 nm), which are gaining importance as biological markers and carriers for cancer therapies, have been proposed to play a critical role in HIV pathogenesis. Recent studies indicate that exosomes secreted from HIV-infected monocytes integrate with adjacent uninfected monocytes and facilitate HIV infection. However, there is nothing known about the role of exosomes in tobacco-mediated HIV pathogenesis and neurotoxicity. The long-term goal of this proposal is to identify the key components of tobacco/HIV-induced exosomes from macrophage/microglia that are responsible for exacerbated HIV pathogenesis and neurotoxicity. Our objective in this proposal is to identify exosomal factors in monocyte-derived macrophages (MDM) and underlying mechanism that are responsible for tobacco-mediated increased HIV replication and neurotoxicity. The central hypothesis is that exosomal components, especially related to oxidative stress pathway, that are released from MDM upon exposure to tobacco constituents are the key mediator for HIV replication and neurotoxicity. We will test the hypothesis as follows. Specific Aim 1: Determine the contribution, and underlying mechanism, of CSC/BaP and HIV in regulating secretion of exosomes/exosomal AOEs from MDM: Our working hypothesis is that exposure of CSC/BaP and HIV to MDM decreases secretion of exosomes and exosomal AOEs through their decreased synthesis. Specific Aim 2: Determine the contribution and underlying mechanism of exosomes/exosomal AOEs towards HIV replication in MDM and neurotoxicity. Our working hypothesis is that exosomes, which are derived from CSC/BaP-treated MDM, increase HIV replication, and exposure of CSC/BaP and HIV together to neuronal cells increases neurotoxicity. Upon successful completion of the proposed research, we will have established that exosomal AOEs derived from CSC/BaP-treated MDM are critical for HIV pathogenesis and neurotoxicity. Such outcome will open a new avenue in understanding the mechanisms of smoking-mediated HIV pathogenesis and neurotoxicity. The knowledge obtained will provide an incentive to evaluate exosomes as biological markers and/or novel carriers for therapies in HIV-infected smokers.

烟草吸烟在艾滋病毒感染的人群中非常普遍，并且已知会加剧HIV 发病。已知对小胶质细胞和巨噬细胞等脑细胞的HIV感染会引起HIV- 50％的艾滋病毒+人群中相关的神经认知障碍（手）。由于烟草成分，主要是 苯并（A）pyrene（BAP）也引起神经毒性，它们可能会进一步加剧HIV-的神经毒性。 感染吸烟者。细胞外囊泡，尤其是外泌体（30-100 nm），它们变得重要 作为癌症疗法的生物标志物和携带者，已被提议在艾滋病毒中发挥关键作用 发病。最近的研究表明，从HIV感染的单核细胞分泌的外泌体与 邻近的未感染的单核细胞并促进HIV感染。但是，对 烟草介导的HIV发病机理和神经毒性中的外泌体。该提议的长期目标是 确定来自巨噬细胞/小胶质细胞的烟草/HIV诱导的外泌体的关键成分 负责加剧的HIV发病机理和神经毒性。我们在此提案中的目标是确定 单核细胞衍生的巨噬细胞（MDM）和基本机制的外泌体因子负责 为了烟草介导的增加HIV复制和神经毒性。中心假设是外泌体 暴露于MDM的组件，特别是与氧化应激途径有关的组件 烟草成分是HIV复制和神经毒性的关键介体。我们将检验该假设为 跟随。具体目标1：确定CSC/BAP和HIV中的贡献和潜在机制 调节MDM的外泌体/外泌体AOE的分泌：我们的工作假设是暴露 CSC/BAP和HIV至MDM可通过减少外泌体和外泌体AOS的分泌 合成。特定目标2：确定的贡献和基本机制 外泌体/外泌体AOE在MDM和神经毒性中复制HIV复制。我们的工作假设是 从CSC/BAP处理的MDM得出的外泌体，增加了HIV复制和暴露 CSC/BAP和HIV共同对神经元细胞增加神经毒性。成功完成后 拟议的研究，我们将确定从CSC/BAP处理的MDM中得出的外泌体AOE是 对于HIV发病机理和神经毒性至关重要。这样的结果将为理解 吸烟介导的HIV发病机理和神经毒性的机制。获得的知识将提供 一种将外泌体评估为生物标记和/或新型疗法的动机 吸烟者。