METHAMPHETAMINE AND HIV PROTEIN-INDUCED NEUROTOXICITY

甲基苯丙胺和 HIV 蛋白引起的神经毒性

• 批准号: 6489495
• 负责人: William F Maragos
• 金额: $ 21.72万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-15 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6489495
• 关键词: HIV envelope protein gp120; HIV infections; clinical research; free radical oxygen; genetically modified animals; human fetus tissue; human immunodeficiency virus; laboratory mouse; laboratory rat; methamphetamine; neurons; neurotoxins; tissue /cell culture; tumor necrosis factor alpha; virus protein

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.

描述：几条证据表明基底神经节是 高度容易感染人类免疫缺陷病毒（HIV）。 但是，基底神经节功能障碍的发病机理尚不清楚。 艾滋病毒感染的患者经常滥用药物，例如甲基苯丙胺，一种药物 众所周知，这也引起长期结构和功能变化 基底神经节。现在有越来越多的证据表明“病毒毒素”（病毒 从感染细胞释放的产品）和甲基苯丙胺共享一个常见的产品 机制，导致神经元损伤。两个这样的产品是艾滋病毒 蛋白质GP120和TAT。在此提案中，我们将研究协同的程度 通过确定这些病毒毒素和甲基苯丙胺之间的严重性 它们会损害体内多巴胺能系统和人类皮质的损害 体外神经元。确定导致神经元的常见机制 功能障碍，最终为细胞死亡，我们还将检查两个 对病毒毒素和MA独立贡献的病理生理过程 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）测量化合物的产生 兴趣（例如，活性氧和TNF-Alpha），并确定 各种抑制剂对神经毒性的功效。完成这些 目标，我们将评估病毒毒素的纹状体内注射的影响 用甲基苯丙胺治疗的动物和人类皮质神经元中的体外 可以操纵细胞类型的地方。