CYTOKINES AND AIDS DEMENTIA COMPLEX

细胞因子和艾滋病痴呆症

• 批准号: 3389592
• 负责人: IAIN Leslie CAMPBELL
• 金额: $ 19.93万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-02-01 至 1996-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3389592
• 关键词: AIDS dementia complex; HIV infections; astrocytes; behavior test; central nervous system disorders; cytokine; electrophysiology; experimental brain lesion; gene expression; genetically modified animals; glial fibrillary acidic protein; gliosis; histopathology; immunocytochemistry; in situ hybridization; interleukin 3; interleukin 6; laboratory mouse; murine encephalomyelitis virus; myelinopathy; neurotropic virus; northern blottings; polymerase chain reaction; psychoneuroimmunology; scrapie; tissue /cell culture; transfection; transfection /expression vector; tumor necrosis factor alpha; wound healing

Individuals infected with the human immunodeficiency virus (HIV) frequently exhibit serious, progressive behavioral, cognitive and motor deficits (termed AIDS Dementia Complex - ADC) in association with pathological changes (including gliosis, encephalitis and vacuolar myelopathy in the brain. Despite widespread neurological deficits, the virus is restricted in distribution to neural cells having a monocyte/macrophage lineage and is thought not to infect neuronal cells, implying that the mechanism of HIV-associated disease is probably indirect, mediated by toxic factors produced as a result of or in response to the viral infection. In this context an attractive hypothesis is that cytokines, produced either by infiltrating immunoinflammatory cells or by resident brain cells, via their ability to regulate the growth and functions of glial and neuronal cells are key mediators of pathology in ADC. This proposal will investigate the effects of three such cytokines - interleukin-6(IL-6), tumor necrosis factor - alpha(TNF-alpha) and interleukin-3(IL-3) to induce CNS pathology in vivo. We will use the transgenic approach to target the expression of IL-6, TNF-alpha proteins to CNS astrocytes in the mouse using a glial fibrillary acidic protein (GFAP) based expression vector. Through this approach we aim to reproduce aspects of the pathology seen in ADC and correlate these with clinical changes. In addition, interactions between pathogenetic factors will be examined in transgenic lines of mice by inducing further CNS insults e.g. stab wound injury or infection with neurotropic agents, as well as crossing lines of mice expressing different transgenes. Finally in order to gain an understanding of the neurological and behavioral impact of over-expressing cytokines in the CNS, transgenic mice will be subject to electrophysiological and behavioral testing. The studies outlined in this proposal will establish murine models to examine the pathophysiological consequences of inappropriately expressing cytokines in the CNS. They should provide important insights into what currently remains a mystery i.e. the molecular basis for ADC.

感染人类免疫缺陷病毒（HIV）的个人 经常表现出严重的、渐进的行为、认知和运动 缺陷（称为艾滋病痴呆症 - ADC）与 病理变化（包括神经胶质增生、脑炎和空泡 大脑中的脊髓病。 尽管存在广泛的神经功能缺陷， 病毒的分布仅限于具有以下特征的神经细胞： 单核细胞/巨噬细胞谱系，被认为不会感染神经元细胞， 这表明 HIV 相关疾病的机制可能是 间接的，由由于或在其中产生的毒性因素介导 对病毒感染的反应。 在这种背景下，一个有吸引力的 假设是细胞因子通过渗透产生 免疫炎症细胞或常驻脑细胞通过其能力 调节神经胶质细胞和神经元细胞的生长和功能是关键 ADC 中的病理介质。 该提案将调查 三种细胞因子的影响 - 白细胞介素 6 (IL-6)、肿瘤坏死 因子-α（TNF-α）和白细胞介素-3（IL-3）诱导中枢神经系统病理学 体内。 我们将使用转基因方法来靶向表达 使用神经胶质细胞将 IL-6、TNF-α 蛋白转化为小鼠中枢神经系统星形胶质细胞 基于纤维酸性蛋白（GFAP）的表达载体。 通过这个 我们的目标是重现 ADC 中所见病理学的各个方面 将这些与临床变化联系起来。 此外，之间的相互作用 将通过以下方法在转基因小鼠系中检查致病因素 诱发进一步的中枢神经系统损伤，例如刺伤或感染 神经营养剂，以及表达的小鼠的杂交系 不同的转基因。 最后为了加深对 过度表达细胞因子对神经和行为的影响 CNS，转基因小鼠将接受电生理和 行为测试。 本提案中概述的研究将确定 小鼠模型来检查病理生理学后果 中枢神经系统中细胞因子的不适当表达。 他们应该提供 对目前仍然是个谜的重要见解，即 ADC 的分子基础。