BRAIN EFFECTS OF INTERFERON ALPHA

艾滋病毒感染的行为影响比 从中央感染的性质和程度预测， 因此，在神经系统中，必须检查细胞因子的可能作用。 因为在患者的血清中发现了一种酸不稳定的干扰素-α（IFN-α）， 艾滋病病毒感染者，并因给予外源性干扰素治疗病毒 感染或肿瘤具有神经心理学效应，这种细胞因子是 建议研究的重点。 我们已经建立了一个小鼠模型， 外源性IFN-α产生HIV感染的一些症状， 治疗;活动减少和厌食。 这一建议涉及到 问题是这种外周产生的细胞因子是如何在中枢神经系统中 方面的影响. 外周给药的IFN-α进入大脑， 金额。 这项建议旨在准确地确定确切数额， IFN-α进入CNS的位置，并确定其是否 集中在脑室周围器官， 屏障薄弱。 首先，将通过去除IFN-α测定来优化IFN-α测定。 干扰IFN检测的因素。 第二，IFN-γ的时间过程 将测定包括脑在内的多种器官中的α滴度。 第三，利用前两次实验的结果，区域 将确定IFN-α在脑中的分布，以评估 假设它作用于室周器官（CVO）， 血脑屏障 第四，IFN-alpha是否应该定位于CVOs， 应足够浓缩，以便能够使用银增强的 胶体金标记IFN定位IFN-γ进入的确切位点， 阿尔法进入大脑。 第五，我们将确定IFN-γ的量是否 进入大脑的α足以产生典型的干扰素效应 在大脑上。来自干扰素特异性基因（鸟苷酸结合蛋白）的mRNA 将通过聚合酶链反应扩增在 发现大脑含有干扰素。 第六，原位杂交将用于 定位GBP-1基因表达，并结合金标记， 的IFN 确定了IFN-α进入CNS的位点， 我们将能够设计未来的研究 IFN-α、IFN调节产物与脑系统相互作用 由于外源性干扰素或病毒而产生的行为效应 感染

The behavioral effects of HIV infection are more extensive than would be predicted from the nature and extent of the infection of the central nervous system, therefore, the possible role of cytokines must be examined. Because an acid-labile interferon-alpha (IFN-alpha) is seen in the serum of HIV infected individuals, and because exogenous IFN given to treat virus infections or tumors has neuropsychological effects, this cytokine is the focus of the proposed studies. We have established in a mouse model that exogenous IFN-alpha produces some of the symptoms of HIV infection and IFN treatment; decreased activity and anorexia. This proposal is concerned with the problem of how this peripherally produced cytokine can have CNS effects. Peripherally administered IFN-alpha enters the brain in small amounts. This proposal seeks to accurately determine the exact amounts and location of entry of IFN-alpha into the CNS and to determine whether it is concentrated around the circumventricular organs where the blood brain barrier is weak. First, the IFN-alpha assay will be optimized by removing factors that interfere with IFN detection. Second, the time course of IFN- alpha titers in a variety of organs, including brain will be determined. Third, using the results of the previous two experiments, the regional distribution of IFN-alpha in the brain will be determined to assess the hypothesis that it acts at the circumventricular organs (CVO) lacking a blood-brain barrier. Fourth, should IFN-alpha be localized to the CVOs it should be concentrated enough to enable detection using silver enhanced colloidal gold-labeled IFN to localize the exact sites of entry of IFN- alpha into the brain. Fifth, we will determine whether the amounts of IFN- alpha that enter the brain are sufficient to have the typical IFN effects upon the brain. mRNA from an IFN-specific gene (guanylate binding protein) will be detected by polymerase chain reaction amplification in areas of the brain found to contain IFN. Sixth, in situ hybridization will be used to localize the GBP-1 gene expression in conjunction with gold labeling of IFN. Having determined the sites of entry of IFN-alpha into the CNS and its ability to act there, we will be able to design future studies on the interaction between IFN-alpha, IFN regulated products and brain systems that produce the behavioral effects due to exogenous IFN or virus infection.