Glial-neuronal interactions underlying the molecular feedback between HIV viral p

HIV病毒p之间分子反馈的胶质神经元相互作用

• 批准号: 8585520
• 负责人: SULIE L. CHANG
• 金额: $ 19.66万
• 依托单位: SETON HALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8585520
• 关键词: AIDS neuropathy; Acquired Immunodeficiency Syndrome; Affect; Animals; Anti-Retroviral Agents; Apoptotic; Area; Astrocytes; Baltimore; Behavior; Behavior Disorders; Behavioral; Blood; Brain; Cell Communication; Cells; Chronic; Clinical; Corpus striatum structure; DRD2 gene; Data; Dementia; Dependence; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Drug Addiction; Enhancers; Exposure to; Fatigue; Feedback; Gagging; Gene Expression; Genes; Genetic Transcription; Goals; HIV-1; Head Movements; Human; Immunohistochemistry; In Vitro; Inbred F344 Rats; Individual; Infection; Inflammation; Inflammatory; Intake; Interleukin-1; Lead; Light; Literature; Maps; Mediating; Mental Depression; Methamphetamine; Microglia; Modeling; Molecular; Motor Activity; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Neurotransmitter Receptor; Neurotransmitters; Nuclear; Organ; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Prefrontal Cortex; Primary Cell Cultures; Production; Proteins; Proviruses; Rat-1; Rattus; Receptor Signaling; Reporting; Research; Rewards; Rodent Model; Substance abuse problem; Synaptic Cleft; System; Testing; Transgenic Organisms; Viral; Viral Load result; Viral Proteins; Virus; base; behavioral sensitization; chemokine; clinically relevant; cytokine; methamphetamine abuse; neuroinflammation; neurotoxicity; painful neuropathy; preference; psychostimulant; public health relevance; receptor; receptor expression; substance abuser; transmission process

DESCRIPTION (provided by applicant): The long-term goal of this research is to delineate the possible mechanisms underlying the increased abuse of substances, such as methamphetamine (METH), by individuals who are human immunodeficiency virus-1 (HIV)-positive. In this two-year exploratory project, we propose to specifically examine the synergistic effects of methamphetamine (METH), an addictive psychostimulant, and HIV-1 viral proteins on glial-neuronal induction of inflammation in the rat brain. In the central nervous system (CNS), the glial cells are infected by the HIV-1 virus, causing neuroinflammation. Increased inflammation in the brain has been correlated with neurodegenerative diseases and behavioral disorders, such as HIV-1 induced neurodegeneration (HAND) and HIV-1 induced dementia (HAD). Moreover, METH abuse in the HIV-infected individual can lead to increased viral loads and severe brain-related disorders. For these studies, we will use both the non-infectious HIV-1 transgenic (HIV-1Tg) rat and primary cell culture models. The HIV-1Tg rat carries a gag/pol deleted provirus gene, and expresses 7 out of 9 HIV-1 viral proteins. This HIV-1Tg rat develops clinical manifestations of human HIV disease, and, thus, mimics the infection that results from the persistent presence of HIV-1 proteins in HIV patients given anti-retroviral therapy. Recently, using PCR array analysis, we showed that the pro- inflammatory cytokine, IL-1¿, as well as the Ccl2, Ccl3, and Ccl7 chemokines, are increased to a greater extent in the brain of the HIV-1Tg rat compared to the F344 control rat. We have also demonstrated that there is elevated dopamine D1 receptor (D1R) expression in the prefrontal cortex of HIV-1Tg rats, and that these animals have greater METH-induced behavioral sensitization, as assessed by stereotypical head movement. Based on the literature and our previous data, we hypothesize that the abuse of substances, such as METH, in the presence of HIV-1 viral proteins, enhances glial activation, which affects neurons, and increases the activity of the dopaminergic system, thereby increasing the intake of METH. To test this hypothesis, we will first examine the glial-neuronal cell interaction in the brain of the HIV-1Tg rat with and without exposure to METH using immunohistochemistry. We will then identify gene expression changes in neurotransmitter activity, in particular, the dopaminergic system, as well as neuroinflammation-related markers. We will also isolate primary glial and neuronal cells from HIV-1Tg rats and examine gene expression changes in the dopaminergic and other neurotransmitter pathways, as well as inflammation, and apoptotic and oxidative stress markers after in vitro exposure to METH. Our specific aims include: 1) To determine the effects of METH and HIV viral proteins on glial and neuronal activation, neuroinflammation, and neurotransmitter modulation in the brain of the HIV-1Tg rat, and 2) To determine the effects of METH and HIV viral proteins on glial and neuronal activation, neuroinflammation, and neurotransmitter modulation in an ex vivo model using primary glial and neuronal cells isolated from the HIV- 1Tg rat brain To our knowledge, this proposal represents the first project to explore the effects of METH on glial-neuronal interactions and the subsequent effects on the dopaminergic system using the HIV-1Tg rat and primary cell cultures isolated from the HIV-1Tg rat. The data from this research will shed light on possible cellular and molecular mechanisms underlying the increased abuse of substances such as METH by HIV-positive individuals, and help to elucidate the glial-neuronal interactions associated with METH abuse and neuroAIDS. Our exploratory studies can also lead to better treatment approaches that will ultimately benefit both HIV-1 patients and substances abusers. Thus, the proposed studies have high clinical relevance and will contribute significantly to the understanding and treatment of neurological complications associated with substance abuse, HIV infection, and AIDS.

描述（由适用提供）：这项研究的长期目标是描述滥用物质滥用的可能机制，例如甲基苯丙胺（甲基苯丙胺（METH）），由人类免疫缺陷病毒-1（HIV）阳性的个体。在这个为期两年的探索性项目中，我们建议特别检查甲基苯丙胺（METH），一种额外的心理刺激剂和HIV-1病毒蛋白对大鼠脑中炎症的神经神经神经元诱导的协同作用。在中枢神经系统（CNS）中，神经胶质细胞被HIV-1病毒感染，导致神经炎症。大脑中的炎症增加与神经退行性疾病和行为疾病有关，例如HIV-1诱导的神经变性（手）和HIV-1诱导的痴呆症（HAD）。此外，在感染HIV的人中滥用甲基苯丙胺会导致病毒载荷增加和严重的与脑有关的疾病。对于这些研究，我们将同时使用非感染性HIV-1转基因（HIV-1TG）大鼠和原发性细胞培养模型。 HIV-1TG大鼠带有插入/pol的病毒基因，并在9个HIV-1病毒蛋白中表达7个。这种HIV-1TG大鼠发展了人类HIV疾病的临床表现，因此模仿了因抗网状病毒疗法而在HIV患者中持续存在HIV-1蛋白引起的感染。最近，使用PCR阵列分析，我们表明与F344对照大鼠相比，HIV-1TG大鼠大脑的大脑中，促炎性细胞因子，IL-1以及CCL2，CCL3和CCL7趋化因子在更大程度上增加了。我们还证明，在HIV-1TG大鼠的前额叶皮层中，多巴胺D1受体（D1R）表达升高，并且这些动物具有较高的甲基甲基甲烷诱导的行为敏感性，如刻板印象的头部运动所评估。根据文献和以前的数据，我们假设在存在HIV-1病毒蛋白的情况下滥用甲基甲基的滥用，增强了神经胶质激活，从而影响神经元，并增加多巴胺能系统的活性，从而增加甲基苯酚的摄入量。为了检验这一假设，我们将首先检查HIV-1TG大鼠大脑中的神经神经元细胞相互作用，并使用免疫组织化学接触或不暴露于METH。然后，我们将确定神经递质活性的基因表达变化，尤其是多巴胺能系统以及与神经炎症相关的标记。我们还将与HIV-1TG大鼠的原发性神经胶质细胞和神经元细胞分离，并检查多巴胺能和其他神经递质途径的基因表达变化，以及炎症，以及体外暴露于MET的炎症和凋亡和氧化应激标记。我们的具体目的包括：1）确定甲基和HIV病毒蛋白对HIV-1TG大鼠脑中神经胶质和神经元激活，神经炎性和神经递质调节的影响，以及2）确定MECH和HIV病毒蛋白对glial和Neurary AnnoRASTRITAIN，NEUROTRITAIN和NEUROT的影响，并确定NEUROT INUROTROT和NEUROTINFLOT，并确定从HIV-1TG大鼠大脑分离到我们所知的神经胶质和神经元细胞，该建议代表了探索甲基甲基神经神经神经元相互作用的第一个项目 以及随后使用HIV-1TG大鼠和从HIV-1TG大鼠分离的原代细胞培养物对多巴胺能系统的影响。这项研究的数据将阐明滥用艾滋病毒阳性个体滥用物质（例如甲基甲基苯酚）的可能的细胞和分子机制，并有助于阐明与甲基甲基苯丙胺滥用和神经辅助相关的神经神经神经元相互作用。我们的探索性研究还可以导致更好的治疗方法，最终将使HIV-1患者和滥用物质受益。这是拟议的研究具有很高的临床相关性，将对与药物滥用，HIV感染和艾滋病相关的神经系统并发症的理解和治疗产生重大贡献。