ETIOLOGIC ROLE OF TNF/FAS ON AN AIDS-LIKE CNS DISEASE

描述（改编自摘要）：本申请的广泛目标 是对艾滋病痴呆症的神经发病机制的重点检查， 复合物（ADC）。他的实验设计依赖于小鼠模型的使用 一种突变的莫洛尼鼠病毒的感染 白血病病毒（MoMuLV）诱导进行性神经免疫变性 与人类有一些临床和病理相似性的疾病（NID） 免疫缺陷病毒1型（HIV 1）相关中枢神经系统（CNS） 疾病该模型与HIV-1感染CNS之间的相似性 包括：（1）免疫系统中T细胞的选择性消耗， CNS中的神经元;（2）CNS星形胶质细胞的感染和过度活化， （3）肿瘤坏死因子（TNF）水平升高 区域;和（4）间接机制导致的神经元损失。的 本申请的具体目的是：（1）确定表达式 TNF、IL-1、Fas/FasL和其他细胞因子在脑干、脊髓和脊髓中的水平 脊髓和大脑皮层的ts 1和WT感染的小鼠和未感染的 并定量脑中产生的TNF浓度 在不同时间点TS 1感染小鼠的脑干和大脑皮层 感染后;（2）确定CNS中哪些细胞类型表达TNF， IL-1、Fas和FasL;哪些细胞类型经历凋亡;以及哪些细胞 型在ts 1感染的小鼠中被ts 1感染;（3）为了确定TNF， IL-1和Fas信号转导是ts 1介导的细胞凋亡的途径。 通过比较疾病进展和神经元损失， ts 1感染的TNFR KO、TNF KO、IL-1 R KO和Fas以及FasL缺陷型 小鼠与相应的未感染KO小鼠和ts 1感染正常小鼠中的那些相比 通过比较TS 1感染小鼠的疾病进展和神经元损失， 用可溶性TNFR、可溶性Fas或可溶性IL-1 R处理的FVB/N小鼠;和（4） 以确定（a）TNF和Fas或（B）TNF和IL-1的联合作用是否 是预防双基因敲除（KO）小鼠疾病发展所必需的 在TNFR 1和Fas均被破坏的纯合小鼠中， TNFR 1和IL-1 R的破坏。TS 1感染的联合治疗 同时具有TNF和FasL或TNF和IL-1的可溶性受体的FVB/N小鼠， 也进行。

DESCRIPTION (adapted from the Abstract): The broad goal of this application is a focused examination of the neuropathogenesis of the AIDS Dementia Complex (ADC). His experimental design relies on the use of a murine model of neurodegeneration in which infection of a mutant form of Moloney Murine Leukemia Virus (MoMuLV) induces a progressive neuroimmunodegenerative disease (NID) that has some clinical and pathological similarities to human immunodeficiency virus type 1 (HIV1)-associated central nervous system (CNS) disease. Similarities between this model and HIV-1 infection of the CNS include: (1) selective depletion of T cells in the immune system and neurons in the CNS; (2) infection and overactivation of CNS astrocytes and microglia; (3) elevated levels of tumor necrosis factor (TNF) in lesion areas; and (4) neuronal loss as a result of indirect mechanisms. The specific aims of this application are: (1) to determine the expression levels of TNF, IL-1, Fas/FasL, and other cytokines in the brain stem, spinal cord, and cerebral cortex of ts1- and WT-infected mice and uninfected controls and to quantitate the concentration of TNF produced in the brain stem and cerebral cortex of ts1-infected mice at various time points postinfection; (2) to determine which cell types in the CNS express TNF, IL-1, Fas, and FasL; which cell types undergo apoptosis; and which cell types are infected by ts1 in ts1-infected mice; (3) to determine if TNF, IL-1, and Fas signal transduction is the pathway utilized in ts1-mediated neurodegeneration by comparing disease progression and neuronal loss in ts1-infected TNFR KO, TNF KO, IL-1R KO, and Fas- as well as FasL-deficient mice with those in respective uninfected KO mice and ts1-infected normal mice and by comparing disease progression and neuronal loss in ts1-infected FVB/N mice treated with soluble TNFR, soluble Fas, or soluble IL-1R; and (4) to determine if the combined action of (a) TNF and Fas or (b) TNF and IL-1 is necessary to prevent disease development in double knock out (KO) mice homozygous for disruption of both TNFR1 and Fas and in mice homozygous for disruption of both TNFR1 and IL-1R. Combined treatments of ts1-infected FVB/N mice with soluble receptors of both TNF and FasL or TNF and IL-1 will also be conducted.