METHAMPHETAMINE AND HIV PROTEIN-INDUCED NEUROTOXICITY

描述：几条证据表明，基底神经节是 非常容易感染人类免疫缺陷病毒（HIV）。 然而，基底神经节功能障碍的发病机制还不清楚。 艾滋病病毒感染者经常滥用药物，如甲基苯丙胺， 众所周知，这也会导致长期的结构和功能变化， 基底神经节现在有越来越多的证据表明，“病毒毒素”（病毒 受感染细胞释放的产物）和甲基苯丙胺有一个共同点， 机制，导致神经元损伤。两种这样的产品是艾滋病毒 gp 120和达特蛋白。在这项建议中，我们会研究协同作用的程度 这些病毒毒素和甲基苯丙胺之间的关系， 它们对体内多巴胺能系统和人类皮质 体外培养的神经元。为了确定导致神经元损伤的共同机制， 功能障碍，并最终导致细胞死亡，我们还将研究两个 病理生理过程，独立贡献病毒毒素和MA 毒性，即活性氧和细胞因子TNF-α。在 研究这两个过程，我们将2）测量化合物的产量， 感兴趣的（例如活性氧和TNF-α），并确定 各种抑制剂对神经毒性的疗效。完成这些 目的，我们将评估纹状体内注射病毒毒素对 用甲基苯丙胺处理的动物和在人皮层神经元中的体外 在那里可以操纵细胞类型。

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.