METHAMPHETAMINE AND HIV PROTEIN-INDUCED NEUROTOXICITY

描述：有几条证据表明，基底神经节 极易感染人类免疫缺陷病毒(HIV)。 然而，基底节功能障碍的发病机制尚不清楚。 艾滋病毒感染者经常滥用药物，如甲基苯丙胺，一种药物 众所周知，这也会导致长期的结构和功能变化 基底节。现在有越来越多的证据表明“病毒毒素”(病毒 从受感染细胞释放的产物)和甲基苯丙胺有共同的 机制，这会导致神经元损伤。两种这样的产品是艾滋病毒 蛋白gp120和Tat。在这项建议中，我们将审查协同的程度 通过确定这些病毒毒素和甲基苯丙胺的严重程度 它们对体内的多巴胺能系统和人类皮质造成损害 体外培养的神经元。找出导致神经细胞的共同机制 功能障碍，并最终导致细胞死亡，我们还将检查两个 对病毒毒素和MA起独立作用的病理生理过程 毒性，即活性氧物种和细胞因子肿瘤坏死因子-α。在……里面 研究这两个过程，我们将2)测量化合物的产量 兴趣(例如，活性氧物种和肿瘤坏死因子-α)，并确定 多种抑制剂对神经毒性的疗效。要实现这些目标 目标，我们将评估纹状体内注射病毒毒素的效果。 甲基苯丙胺处理的动物和体外培养的人皮质神经元 在那里细胞类型可以被操纵。

DESCRIPTION: Several lines of evidence indicate that the basal ganglia are highly susceptible to infection with the human immunodeficiency virus (HIV). However, the pathogenesis of basal ganglia dysfunction is not well understood. Patients with HIV infection often abuse drugs such as methamphetamine, a drug that is well known to also cause long-term structural and functional changes to the basal ganglia. There is now mounting evidence that "virotoxins" (viral products released from infected cells) and methamphetamine share a common mechanism, which leads to neuronal damage. Two such products are the HIV proteins gp120 and Tat. In this proposal, we will examine the degree of synergy between these virotoxins and methamphetamine by determining the severity of damage they cause to the dopaminergic system in vivo and to human cortical neurons in vitro. To identify common mechanisms that lead to neuronal dysfunction and ultimately, to cell death, we will also examine two pathophysiological processes that contribute independently to virotoxin and MA toxicity, namely reactive oxygen species and the cytokine TNF-alpha. In studying these two processes, we will 2) measure production of compounds of interest (e.g. reactive oxygen species and TNF-alpha) and determine the efficacy of a variety of inhibitors on neurotoxicity. To accomplish these goals, we will assess the effects of intrastriatal injections of virotoxins in animals treated with methamphetamine and in vitro in human cortical neurons where cell types can be manipulated.