Regulation of HIV and opiate-directed synaptodendritic injury/death in striatum

描述（由申请人提供）：将探讨阿片类药物和HIV-1相互作用对纹状体神经元和潜在的细胞内信号通路（自噬，内质网应激/未折叠蛋白反应（UPR），细胞凋亡）导致亚致死损伤和死亡的神经毒性后果。越来越多的证据表明，阿片类药物滥用本身直接加剧了HIV-1的神经病理。我们发现(1)阿片类药物通过独立作用于？-阿片受体（MOR）表达神经元、星形胶质细胞和小胶质细胞；(2)在神经元死亡之前，突触树突病理发生了非致命性的变化，这些变化可能是可逆的。阿片类药物滥用在很大程度上/完全通过协同破坏神经胶质功能和树突病理来增强HIV的神经发病机制。我们假设，阿片- hiv相互作用增加神经元死亡之前，对突触组织和功能的累积损伤起源于胶质细胞，是非致命的，并且假定是可逆的。这些神经元功能的减少可能是神经艾滋病认知障碍的基础，并代表了慢性药物滥用- hiv合并症的重要治疗靶点。目的1将使用多种体外模型，包括原代人游离神经元、星形胶质细胞和小胶质细胞培养，检查阿片类药物和hiv -1依赖性（Tat、gp120和活病毒）亚致死性神经元功能障碍和/或死亡作为一个连续体。细胞凋亡、自噬和内质网应激/UPR可能在亚致死损伤和神经元死亡过程中起作用，这些途径被评估和测试潜在的可逆作用。目的2将确定凋亡、自噬和内质网应激/UPR事件在多大程度上与阿片类hiv诱导的神经元功能障碍和/或体内死亡相关。我们在活的、培养的神经元中可视化/操纵凋亡、自噬和UPR事件的能力将为阿片类药物滥用/HIV共病的发病机制提供新的见解，并将揭示逆转神经元损伤的新策略。我们的实验室是第一个证明阿片类药物，在很大程度上通过胶质中间体，加剧艾滋病毒诱导的中枢神经系统神经免疫反应和神经元损伤。我们的长期目标是确定阿片类药物使用或滥用导致HIVE伴有神经退行性变的机制，并确定可能针对治疗干预的信号通路。

DESCRIPTION (provided by applicant): The neurotoxic consequences of opiate drug and HIV-1 interactions on striatal neurons and on the underlying intracellular signaling pathways (autophagy, ER-stress/unfolded protein responses (UPR), apoptosis) resulting in sublethal injury and death will be explored. Accumulating evidence indicates that opioid drug abuse per se directly exacerbates the neuropathology of HIV-1. We have found that (1) opioid drugs exacerbate neuronal injury and death through independent actions on ?-opioid receptor (MOR) expressing neurons, astroglia and microglia; and (2) that neuronal death is preceded by non-lethal changes in synaptodendritic pathology that are presumably reversible. Opiate abuse potentiates the neuropathogenesis of HIV largely/exclusively by synergistically disrupting glial function and dendritic pathology. We hypothesize that opioid-HIV interactive increases in neuron death are preceded by cumulative insults to synaptic organization and function that originate in glia, are non-lethal, and assumed reversible. These reductions in neuronal function likely underlie cognitive impairment in neuroAIDS and represent an important therapeutic target for chronic drug abuse-HIV comorbidity. Aim 1 will examine opioid and HIV-1-dependent (Tat, gp120, and live virus) sublethal neuronal dysfunction and/or death as a continuum using multiple in vitro models including primary human dissociated neuron, astroglia, and microglial cultures. It is likely that apoptosis, autophagy, and ER-stress/UPR are operative in sublethal injury as well as during neuron death, and these pathways are evaluated and tested for potentially reversible effects. Aim 2 will identify the extent to which apoptotic, autophagic, and ER-stress/UPR events are associated with opiate-HIV-induced neuronal dysfunction and/or death in vivo. Our ability to visualize/manipulate apoptotic, autophagic, and UPR events in living, cultured neurons will garner new insight into the pathogenesis of opioid abuse/HIV comorbidity and will reveal novel strategies to reverse neuron injury. Our labs were the first to show that opioids, in large part via glial intermediates, exacerbate HIV-induced CNS neuroimmune responses and neuronal injury. Our long-term goal is to define the mechanisms by which opiate drug use or abuse contributes to neurodegeneration accompanying HIVE, and to identify signaling pathways that could be targeted for therapeutic intervention.