CYTOKINES AND AIDS DEMENTIA COMPLEX

感染人类免疫缺陷病毒(HIV)的个人 经常表现出严肃、进步的行为、认知和运动 与以下疾病相关的缺陷(称为艾滋病痴呆症-ADC) 病理改变(包括胶质细胞增多症、脑炎和空泡 脑部脊髓病。尽管普遍存在神经缺陷，但 病毒仅限于分布于具有 单核/巨噬细胞谱系，被认为不会感染神经细胞， 这意味着HIV相关疾病的机制可能是 间接的，由因以下原因而产生的毒性因素所调节的 对病毒感染的反应。在这一背景下，一个有吸引力的 假说是细胞因子，要么是通过渗透产生的 免疫炎症细胞或常驻脑细胞，通过它们的能力 调节神经胶质细胞和神经细胞的生长和功能是关键 ADC中的病理介质。这项提案将调查 三种细胞因子白介素6在肿瘤坏死中的作用 肿瘤坏死因子-α和白介素3诱导中枢神经系统病理 在活体内。我们将使用转基因方法来靶向表达 小鼠中枢神经系统星形胶质细胞表达IL-6、TNF-α蛋白的研究 纤维酸性蛋白(GFAP)表达载体。通过这件事 我们的目标是再现ADC和ADC的病理方面 将这些与临床变化联系起来。此外，两国之间的互动 将通过以下方法在转基因小鼠品系中检测致病因素 导致进一步的中枢神经系统侮辱，例如刺伤或感染 神经促进剂，以及表达基因的小鼠的交叉线 不同的转基因。最后为了更好地理解 过度表达细胞因子对大鼠神经和行为的影响 CNS，转基因小鼠将受到电生理和 行为测试。本提案中概述的研究将建立 建立小鼠模型以研究其病理生理学后果 中枢神经系统中细胞因子表达不当。他们应该提供 对目前仍是一个谜的东西的重要见解，即 ADC的分子基础。

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.