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

描述（由申请方提供）：将探索阿片类药物和HIV-1相互作用对纹状体神经元和潜在细胞内信号通路（自噬、ER应激/未折叠蛋白反应（UPR）、细胞凋亡）的神经毒性后果，导致亚致死性损伤和死亡。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的神经病理学。我们已经发现：（1）阿片类药物通过独立作用于？阿片样物质受体（莫尔）表达神经元、星形胶质细胞和小胶质细胞;和（2）神经元死亡之前是突触树突病理学的非致死性变化，其推测是可逆的。阿片类药物滥用通过协同破坏神经胶质功能和树突病理学，在很大程度上/完全地增强了HIV的神经发病机制。我们假设，阿片类药物-艾滋病病毒的相互作用增加神经元死亡之前的累积损伤的突触组织和功能，起源于神经胶质细胞，是非致命的，并假定可逆的。这些神经元功能的降低可能是神经艾滋病认知障碍的基础，也是慢性药物滥用-HIV合并症的重要治疗靶点。目标1将使用多种体外模型（包括原代人解离神经元、星形胶质细胞和小胶质细胞培养物），研究阿片类药物和HIV-1依赖性（达特、gp 120和活病毒）亚致死性神经元功能障碍和/或死亡。凋亡、自噬和ER-应激/UPR可能在亚致死损伤以及神经元死亡期间起作用，并且这些途径被评估和测试潜在的可逆作用。目的2将确定在何种程度上凋亡，自噬，和ER-应激/UPR事件与阿片类药物-HIV-诱导的神经元功能障碍和/或死亡在体内。我们能够可视化/操纵活的培养神经元中的凋亡、自噬和UPR事件，这将为阿片类药物滥用/HIV合并症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表明阿片类药物，在很大程度上通过神经胶质中间体，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的使用或滥用导致伴随HIVE的神经退行性变的机制，并确定可用于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.