Interactive effects of Meth, HIV and cART on astrocyte/neuron function

冰毒、HIV 和 cART 对星形胶质细胞/神经元功能的相互作用

• 批准号: 9750018
• 负责人: XIU-TI HU
• 金额: $ 49.59万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750018
• 关键词: AIDS/HIV problem; Acute; Address; Adult; Affect; Agonist; Amines; Anti-HIV Therapy; Astrocytes; Biological; Brain; Brain region; Cells; Chronic; Cognition; Combined Modality Therapy; Comorbidity; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dopamine; Dose; Electrophysiology (science); Euphoria; Exposure to; Glutamates; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Human; Human Activities; Immunohistochemistry; In Vitro; Inflammation; Injections; Knowledge; Laboratory Animals; Lamivudine; Maintenance; Mathematics; Medial; Mediating; Medicine; Methamphetamine; Methamphetamine dependence; Modeling; Neuroglia; Neuronal Plasticity; Neurons; Outcome; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Pilot Projects; Play; Potassium Channel; Prefrontal Cortex; Proteins; Protocols documentation; Rattus; Relapse; Research; Resources; Self Administration; Signal Pathway; Testing; Training; Transgenic Organisms; Treatment Efficacy; Western Blotting; Withdrawal; abacavir; addiction; antiretroviral therapy; base; brain dysfunction; craving; dopaminergic neuron; drug abuser; drug of abuse; drug seeking behavior; drug testing; experience; extracellular; fetal; hippocampal pyramidal neuron; immune activation; improved; in vivo; methamphetamine abuse; methamphetamine effect; neurotoxicity; neurotransmission; novel; patch clamp; psychostimulant; receptor; reuptake; side effect

ABSTRACT Despite long-term combined antiretroviral therapy (cART), HIV+ drug abusers experience more severe and rapid progression of HIV-associated neurocognitive disorders (HAND). Methamphetamine (Meth) is a potent stimulant, which is highly abused in the USA, and associated with chronic systemic inflammation. Understanding the mechanism(s) by which Meth and HIV induce pathologies in the brain, whether and how chronic cART alters astrocyte/neuron function in the CNS, and whether Math (or other stimulants) affects cART, is critical for improving current, and developing new effective therapeutic strategies for treating Meth addiction and its comorbid conditions with HIV/AIDS. The medial prefrontal cortex (mPFC) is one of the key regulators of cognition and addiction; but it is profoundly altered following chronic Meth and HIV exposure in vivo with disrupted dopamine (DA) neurotransmission and immune activation of astrocytes. Both human and laboratory animal studies demonstrate that the mPFC dysregulation is significantly implicated in chronic Meth-induced brain dysfunction, associated with euphoria, craving, drug-taking and relapse. Cumulating evidence also indicates that both astrocytes and glutamatergic pyramidal neurons in the PFC are altered after chronic Meth or HIV exposure. Chronic Meth in vivo induces astrocytic and neuronal plasticity that differs from changes induced by acute Meth in vitro; but the underlying mechanism(s) of either one is not fully understood. In this proposed study, we will elucidate a novel, trace amine-associated receptor 1 (TAAR1)-mediated mechanism, by which acute Meth in vitro alters astrocyte activity; and determine alterations in this mechanism after Meth self-administration (Meth-SA) followed by a withdrawal (that elicits drug-seeking), in HIV-1 transgenic (Tg) or non-Tg rats. Moreover, we will also determine whether and how chronic cART in vivo affects functional activity of mPFC astrocytes and neurons; and whether such cART effects are altered by Meth-SA in the context of neuroHIV. Specifically, we will first define the mechanism by which chronic Meth in vivo alters astrocyte function (Aim1). We then will determine the mechanism by which Meth/HIV impacting on mPFC astrocytes/ neurons (Aim2). Finally, we will identify chronic effects of cART (using a fixed-dose combination of abacavir, dolutegravir and lamivudine) in vivo on mPFC astrocytes/neurons, and whether chronic Meth-SA alters them (Aim3). To prove the fundamental base of this proposed research, we provide justification, related citations, and preliminary data to support the Scientific Premise, Scientific Rigor, Relevant Biological Variables, and Resource Authentication for this proposal. Outcomes from the proposed research will reveal the novel, TAAR1- mediated mechanism that plays a key role in underlying the comorbid Meth/HIV impact, and chronic cART effects, on altering astrocytes and pyramidal neurons in the mPFC. This will advance our understanding for interactive effects of Meth, HIV and cART in the CNS, and therefore will induce a strong impact to the field.

抽象的 尽管长期联合抗逆转录病毒疗法（CART），HI​​V+滥用药物的经历更加严重，并且 艾滋病毒相关神经认知障碍的快速进展（手）。甲基苯丙胺（甲基苯丙胺）是一种有效的 刺激剂，在美国高度滥用，与慢性全身炎症有关。 了解甲基苯和艾滋病毒在大脑中诱导病理学的机制，是否以及如何 慢性车在中枢神经系统中改变星形胶质细胞/神经元的功能，以及数学（或其他兴奋剂）是否影响推车， 对于改善电流和制定新的有效治疗策略至关重要 及其与艾滋病毒/艾滋病的合并条件。内侧前额叶皮层（MPFC）是关键调节器之一 认知和成瘾；但是在体内慢性甲基甲基苯丙胺和艾滋病毒暴露后，它被深刻改变 破坏的多巴胺（DA）神经传递和星形胶质细胞的免疫激活。人类和实验室 动物研究表明，MPFC失调显着与慢性甲基诱导的 脑功能障碍，与欣快，渴望，吸毒和复发有关。也累积证据 表明在慢性甲基甲基苯丙胺后，PFC中的星形胶质细胞和谷氨酸能源锥体神经元都会改变 或艾滋病毒暴露。体内慢性甲基甲基甲基甲基苯甲酸甲酯诱导与变化不同 体外由急性甲基诱导；但是，任何一种的基本机制尚未完全理解。在这个 拟议的研究，我们将阐明一种新型的，痕量胺相关的受体1（TAAR1）介导的机制， 急性甲基体外的急性甲基体现了星形胶质细胞的活性；并确定甲基苯丙胺后这种机制的改变 在HIV-1转基因（TG）或 非TG大鼠。此外，我们还将确定体内慢性购物车是否以及如何影响功能活动 MPFC星形胶质细胞和神经元；以及在 Neurohiv。具体而言，我们将首先定义慢性甲基体内变化星形胶质细胞的机制 功能（AIM1）。然后，我们将确定对MPFC星形胶质细胞/甲基毒素影响的机制 神经元（AIM2）。最后，我们将确定CART的慢性效应（使用Abacavir的固定剂量组合， DoluteGravir和Lamivudine）在MPFC星形胶质细胞/神经元上的体内，以及慢性甲基-SA是否改变它们 （AIM3）。为了证明这项拟议研究的基本基础，我们提供了相关的理由，相关的引用， 和初步数据，以支持科学前提，科学严谨，相关的生物学变量和 该建议的资源认证。拟议研究的结果将揭示小说Taar1- 介导的机制在合并症甲基/艾滋病毒撞击和慢性推车方面起着关键作用 影响MPFC中的星形胶质细胞和锥体神经元的影响。这将提高我们对 中枢神经系统中甲基苯丙胺，艾滋病毒和卡车的互动效应，因此将对该领域产生强大的影响。