Methamphetamine and HIV interactions in the regulation of glial activation

甲基苯丙胺和艾滋病毒在神经胶质激活调节中的相互作用

• 批准号: 9480123
• 负责人: Maria Cecilia Garibaldi Marcondes
• 金额: $ 0.85万
• 依托单位: SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9480123
• 关键词: Address; Affect; Amphetamine Users; Astrocytes; Behavior; Binding; Binding Sites; Blood - brain barrier anatomy; Brain; CCR5 gene; CREB1 gene; Cell Line; Cells; Characteristics; Coculture Techniques; Data; Disease Progression; Dopamine; Dose; Elements; Equilibrium; Generations; Genes; Genetic Transcription; Glial Fibrillary Acidic Protein; HIV; HIV Infections; HIV-1; Immune; In Vitro; Infection; Infiltration; Inflammatory; Inflammatory Response; Injectable; Investigation; Macaca; Mediating; Methamphetamine; Microglia; Mus; Neuraxis; Neuroglia; Neurons; Nuclear Translocation; Pathology; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Play; Population; Predisposition; Process; RANTES; Reactive Oxygen Species; Regulation; Regulatory Element; Role; SIV; Signal Induction; Signal Transduction; Small Interfering RNA; Symptoms; System; TATA Box; Transcription Factor AP-1; Transcriptional Activation; Transgenic Mice; Up-Regulation; Ursidae Family; Viral Load result; Virus; Virus Replication; Western Blotting; base; brain cell; chemokine; chemokine receptor; drug of abuse; glial activation; high risk behavior; immune function; immunocytochemistry; immunological status; in vivo; inflammatory marker; inflammatory milieu; inflammatory modulation; macrophage; methamphetamine abuse; methamphetamine use; neuroAIDS; neuropathology; novel; promoter; public health relevance; transcription factor; Address; Affect; Amphetamine Users; Astrocytes; Behavior; Binding; Binding Sites; Blood - brain barrier anatomy; Brain; CCR5 gene; CREB1 gene; Cell Line; Cells; Characteristics; Coculture Techniques; Data; Disease Progression; Dopamine; Dose; Elements; Equilibrium; Generations; Genes; Genetic Transcription; Glial Fibrillary Acidic Protein; HIV; HIV Infections; HIV-1; Immune; In Vitro; Infection; Infiltration; Inflammatory; Inflammatory Response; Injectable; Investigation; Macaca; Mediating; Methamphetamine; Microglia; Mus; Neuraxis; Neuroglia; Neurons; Nuclear Translocation; Pathology; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Play; Population; Predisposition; Process; RANTES; Reactive Oxygen Species; Regulation; Regulatory Element; Role; SIV; Signal Induction; Signal Transduction; Small Interfering RNA; Symptoms; System; TATA Box; Transcription Factor AP-1; Transcriptional Activation; Transgenic Mice; Up-Regulation; Ursidae Family; Viral Load result; Virus; Virus Replication; Western Blotting; base; brain cell; chemokine; chemokine receptor; drug of abuse; glial activation; high risk behavior; immune function; immunocytochemistry; immunological status; in vivo; inflammatory marker; inflammatory milieu; inflammatory modulation; macrophage; methamphetamine abuse; methamphetamine use; neuroAIDS; neuropathology; novel; promoter; public health relevance; transcription factor

DESCRIPTION (provided by applicant): HIV-1 exposure is associated with methamphetamine (Meth) abuse. These two factors synergize in aggravating neuroAIDS symptoms and disease progression. One of the important consequences of Meth on innate immune cells is to change the balance of reactive oxygen species (ROS) and induce inflammatory markers, such as CCR5 and RANTES. These changes are believed to be dopamine-dependent, but we have observed that both ROS and CCR5 can be induced in dopamine-free systems. Interestingly, ROS in the CNS can signal the increase of NFkB levels and phosphorylation, and directly induce activation of promoters of inflammatory molecules. On the other hand, HIV Tat, which also induces ROS, has been shown to potentiate glial activation and neuronal damage induced by Meth and other drugs of abuse. HIV Tat, but not Meth, increases several TATA-box binding components in macrophages in vitro, suggesting that it can have a modulatory effect on promoters of inflammatory molecules that bear a TATA-box promoter domain in the promoter. We hypothesize that transcriptional signaling triggered by Meth-induced ROS interact with a TATA-box-dependent modulatory mechanism in the presence of HIV Tat. We propose to explore the role of ROS-induced pathways in the upregulation of CCR5 and RANTES on astrocytes and microglia by Meth and Tat, aiming to identify the players in a dopamine-independent mechanism. We will also investigate whether the induction of TATA-box binding elements is at the basis of the ability of HIV Tat to modulate ROS and inflammatory markers in the CNS, affect immune cell infiltration and interfere with drug-related stereotypic behaviors. Using an original approach we expect to unveil a basic mechanism of interaction between HIV and Meth in the aggravation of CNS pathology, which will open a new line of investigation with a translational reach.

描述（由申请人提供）：HIV-1暴露与甲基苯丙胺（甲基苯丙胺）滥用有关。这两个因素在加剧神经辅助症状和疾病进展方面协同作用。 METH对先天免疫细胞的重要后果之一是改变活性氧（ROS）的平衡，并诱导炎症标志物（例如CCR5和Rantes）。这些变化被认为是多巴胺依赖性的，但我们已经观察到ROS和CCR5均可在无多巴胺系统中诱导。有趣的是，中枢神经系统中的ROS可以指示NFKB水平和磷酸化的增加，并直接诱导炎症分子启动子的激活。另一方面，也显示出诱导ROS的HIV TAT会增强神经胶质激活和由METH和其他滥用药物引起的神经元损害。 HIV TAT（而不是Meth）在体外增加了巨噬细胞中的几种TATA-box结合成分，这表明它可以对带有TATA-Box启动子结构域中启动子的炎性分子的启动子产生调节作用。我们假设在HIV TAT存在下，由Meth诱导的ROS触发的转录信号与TATA-Box依赖性调节机制相互作用。我们建议探索ROS诱导的途径在CCR5和RANTES上的上调在星形胶质细胞和小胶质细胞上的作用，旨在鉴定多巴胺独立的机制中的参与者。我们还将研究TATA-box结合元件的诱导是否是基于HIV TAT调节CNS中ROS和炎症标志物的能力，影响免疫细胞浸润并干扰与药物相关的刻板印象。使用原始方法，我们期望在CNS病理学加重中揭示HIV和METH之间相互作用的基本机制，该病理将开启以转化范围的新研究。