Project 3

项目3

• 批准号: 6594213
• 负责人: IAIN Leslie CAMPBELL
• 金额: $ 35.07万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6594213
• 关键词: AIDS /HIV neuropathy; HIV envelope protein gp120; drug interactions; genetically modified animals; interferons; interleukin 6; laboratory mouse; methamphetamine; neurotoxins; oxidative stress; pathologic process; proteolysis; tumor necrosis factor alpha; virus infection mechanism

Individual's infected with the human immunodeficiency virus (HIV-1) frequently exhibit serious, progressive behavioral, cognitive and motor deficits (termed NeuroAIDS) in association with pathological changes (including gliosis, encephalitis and vacuolar myelopathy) in the brain. Current evidence strongly indicate the pathogenesis of this disorder (also known as NeuroAIDS) involves neurotoxic pathways mediated by: (1) HIV-1 related products e.g. the envelope protein gp120 and (2) products of the host response exemplified by cytokines such as IL-6, IFN- and TNF, release from activated macrophage/microglia and astroglia. Methamphetamine (METH) abuse which is frequently accomplished by significant acute and long-term neuronal damage is prevalent amongst HIV-1 infected individuals. We hypothesize here that the combination of these viral, host and METH insults produce additive or even synergistic actions that result in the worsening of the neuropathological sequelae and an accelerated progression to the functional neuropsychiatric deficits of NeuroAIDS. To determine the nature and mechanisms by which the central stimulant drug METH interacts with host-derived and HIV-1 related products to influence the degree and progression of structural and functional central nervous system (CNS) injury. Dysregulated peripheral immune function resulting from HIV-1 infection as well as infection from additional infectious agents is observed in individuals with AIDS. Therefore, we will define the interactions between METH and peripheral immune stimulation (achieved by intraperitoneal injection of the potent immune stimulant lipopolysaccharide) to influence the severity and progression of both CNS host responses and neuropathology. Transgenic mice with cerebral expression of IL6, TNF-, TNF- or gp120 recapitulate many of the structural and functional features of NeuroAIDS and will be used in the proposed studies to elucidate the interactions between METH and the central production of host- or HIV-1- related products to the development and progression of CNS host responses and neuropathology. Finally, transgenic mice with over-expression of Cu/Zn superoxide dismutase (SOD) or deficient expression of tissue-type plasminogen activator (tPA) that may underlie the pathogenic interactions between METH and products of the host response or HIV-1. This research plan integrates analysis of drug effects on the CNS as it relates to components of HIV disease progression is an important question for pre clinical and clinical research, as substance abusers have a high risk for exposure to the virus. The proposed studies should go far in identifying critical viral- and host-derived factors associated with increased susceptibility to the pathological effects of drugs of abuse such as METH and consequent neurotoxicity.

感染人类免疫缺陷病毒 (HIV-1) 的个体经常表现出严重的、进行性的行为、认知和运动缺陷（称为神经艾滋病），并伴有大脑病理变化（包括神经胶质增生、脑炎和空泡性脊髓病）。目前的证据强烈表明这种疾病（也称为 NeuroAIDS）的发病机制涉及由以下因素介导的神经毒性途径：（1）HIV-1 相关产品，例如艾滋病毒。包膜蛋白 gp120 和 (2) 宿主反应的产物，例如 IL-6、IFN-和 TNF 等细胞因子，从活化的巨噬细胞/小胶质细胞和星形胶质细胞中释放。甲基苯丙胺 (METH) 滥用在 HIV-1 感染者中很普遍，这种滥用通常会造成严重的急性和长期神经元损伤。我们在此假设，这些病毒、宿主和冰毒攻击的结合会产生累加甚至协同作用，导致神经病理学后遗症恶化，并加速进展为 NeuroAIDS 的功能性神经精神缺陷。确定中枢兴奋剂药物 METH 与宿主源性和 HIV-1 相关产物相互作用的性质和机制，以影响中枢神经系统 (CNS) 结构和功能损伤的程度和进展。在艾滋病患者中观察到由 HIV-1 感染以及其他传染源感染导致的外周免疫功能失调。因此，我们将定义冰毒和外周免疫刺激（通过腹腔注射强效免疫刺激脂多糖实现）之间的相互作用，以影响中枢神经系统宿主反应和神经病理学的严重性和进展。脑部表达 IL6、TNF-、TNF- 或 gp120 的转基因小鼠重现了 NeuroAIDS 的许多结构和功能特征，并将在拟议的研究中用于阐明 METH 与宿主或 HIV-1 相关产物的中央产生之间的相互作用，从而影响中枢神经系统宿主反应和神经病理学的发展和进展。最后，转基因小鼠过度表达铜/锌超氧化物歧化酶 (SOD) 或组织型纤溶酶原激活剂 (tPA) 表达不足，这可能是 METH 与宿主反应产物或 HIV-1 之间致病相互作用的基础。该研究计划整合了药物对中枢神经系统的影响分析，因为它与艾滋病毒疾病进展的组成部分有关，这是临床前和临床研究的一个重要问题，因为药物滥用者接触该病毒的风险很高。拟议的研究应该在确定与滥用药物（如冰毒）的病理效应和随之而来的神经毒性的易感性增加相关的关键病毒和宿主衍生因素方面发挥重要作用。