CYTOKINES AND AIDS DEMENTIA COMPLEX

感染人类免疫缺陷病毒（艾滋病毒）的人 经常表现出严重的，渐进的行为，认知和运动 艾滋病痴呆综合征（ADC） 病理改变（包括神经胶质增生、脑炎和空泡 脑脊髓病 尽管存在广泛的神经功能缺陷， 病毒仅限于分布于具有 单核细胞/巨噬细胞谱系并且被认为不感染神经元细胞， 这意味着HIV相关疾病的机制可能是 间接的，由由于或在 对病毒感染的反应。 在这种情况下，一个有吸引力的 假设是细胞因子，通过浸润产生， 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 三种这样的细胞因子-白细胞介素-6（IL-6）、肿瘤坏死因子 因子-α（TNF-α）和白细胞介素-3（IL-3）诱导CNS病理 in vivo. 我们将使用转基因方法来靶向表达 IL-6、TNF-α蛋白与小鼠中枢神经系统星形胶质细胞的关系 基于胶质酸性蛋白（GFAP）的表达载体。 通过这个 我们的目的是再现ADC中所见的病理学方面， 与临床变化相关联。 此外， 致病因素将在转基因小鼠系中进行检查， 诱导进一步的CNS损伤，例如刺伤或感染 神经营养剂，以及交叉线的小鼠表达 不同的转基因 最后，为了了解 过度表达的细胞因子对神经和行为的影响 CNS，转基因小鼠将进行电生理和 行为测试 本提案中概述的研究将建立 小鼠模型，以检查 在CNS中不适当地表达细胞因子。 他们应该提供 重要的见解，目前仍然是一个谜，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.