Drugs of Abuse and NeuroAIDS: Proteome Activity Profiles

描述（由申请人提供）：自引进高效抗逆转录病毒疗法（HAART）以来的十年里，在大多数发达社会中，大多数艾滋病患者的临床病程的严重程度得到了改善。然而，在发展中国家，艾滋病的发病率和临床严重程度继续呈指数增长，部分原因是通过静脉注射药物无意中暴露于HIV-1。在斯克里普斯研究所（DA12444）现有的nida支持的项目中，我指导了一系列研究，利用几种神经艾滋病动物模型来研究病毒诱导的神经发病机制和滥用药物之间潜在的毒性相互作用。我们现在有强有力的证据表明，在这些动物模型中，甲基苯丙胺诱导的毒性与神经艾滋病的进展之间存在积极的相互作用，即协同作用。这种协同作用的机制尚不清楚，但可能部分涉及直接毒性病毒产物（如gp120）与靶向神经元和/或神经胶质的宿主衍生因子的相互作用，以及与药物相关的氧化应激和氧化还原平衡丧失引起的细胞过程受损。

DESCRIPTION (provided by applicant): In the decade since the introduction of highly affective anti-retroviral therapy (HAART), the severity of the clinical course of AIDS has been ameliorated for a majority of afflicted individuals in most developed societies. However, in the developing world the incidence and clinical severity of AIDS continues in an exponential fashion fueled, in part, by inadvertent HIV-1 exposure through intravenous drug use. In an existing NIDA-supported Program Project at the Scripps Research Institute (DA12444), I direct a series of studies employing several animal models of neuroAIDS that investigate the potential toxic interaction between viral-induced neuropathogenesis and drugs of abuse. We now have strong evidence of a positive interaction, i.e. synergy, between methamphetamine-induced toxicity and the progression of NeuroAIDS in these animal models. The mechanisms underlying this synergy are not apparent but may, in part, involve interactions of directly toxic viral products (i.e. gp120) with host-derived factors targeting neurons and/or glib, and with compromised cellular processes precipitated by drug-related oxidative stress and loss of redox poise. In this CEBRA application we propose to initiate a new series of studies that will conceptually extend the current line of investigation that could better elucidate the cellular and molecular mechanisms that lead to the toxic synergism between viral products, host-derived factors and drugs of abuse. The proposed research plan involves a very new chemical approach that utilizes a novel form of proteomic analysis in which the activation state of specific proteins (enzymes) will be characterized and quantified in two accepted animal models of AIDS-related neuropathogenesis in the context of methamphetamine exposure. These new methods, pioneered at The Scripps Research Institute, take advantage of the fact that activation states of specific enzyme families are a more accurate reflection of the functional state of proteins than are protein levels per se. Genetically engineered mice over-expressing either the HIV-1 viral coat protein, gp120, or the host-derived, immune-related cytokine, IL-6, in astrocytes, will be used to compare and contrast the activity states of enzymes involved in these two independent models of AIDS-related neuropathogenesis. These studies will comprise the first proteome activity analysis of these of neuroAIDS models, and will provide a unique molecular profile of the neurotoxic synergy elicited by methamphetamine.