BRAIN EFFECTS OF INTERFERON-ALPHA

艾滋病毒感染对行为的影响比预期的更广泛。 从中原地区感染的性质和程度预测 因此，必须研究细胞因子在神经系统中的可能作用。 因为在慢性阻塞性肺疾病患者的血清中发现了一种不稳定酸的干扰素-α HIV感染者，因给予外源性干扰素治疗病毒 感染或肿瘤有神经心理影响，这种细胞因子是 拟议研究的重点。我们已经在一只小鼠模型中建立了 外源性干扰素-α会产生一些艾滋病毒感染和干扰素的症状 治疗；活动减少和厌食症。这项建议涉及到 这种外周产生的细胞因子如何产生中枢神经系统的问题 效果。外周给药的干扰素-α以小剂量进入大脑 金额。这项建议旨在准确确定准确的金额和 干扰素-α进入中枢神经系统的位置并确定它是否 集中在脑室周围器官，在那里血液脑 屏障很弱。首先，干扰素-α检测将通过去除 影响干扰素检测的因素。第二，干扰素的时间进程- 将测定包括大脑在内的各种器官中的阿尔法滴度。 第三，利用前两个实验的结果，区域 将测定干扰素-α在大脑中的分布，以评估 假设它作用于脑室周围器官(CVO) 血脑屏障。第四，干扰素-α是否应该本地化到CVO？ 应足够浓缩，以便能够使用增强的银色进行检测 胶体金标记干扰素定位干扰素的准确进入部位 阿尔法进入大脑。第五，我们将确定干扰素的量是否- 进入大脑的阿尔法足以产生典型的干扰素效应 对大脑的影响。来自干扰素特异性基因(鸟苷结合蛋白)的mRNA 将通过聚合酶链式反应扩增检测到 大脑中发现含有干扰素。第六，将采用原位杂交技术 结合金标记法定位GBP-1基因的表达 干扰素。在确定了干扰素-α进入中枢神经系统和 它在那里发挥作用的能力，我们将能够设计未来关于 干扰素-α及其调控产物与脑系统的相互作用 因外源性干扰素或病毒而产生行为影响的 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.