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

描述(改编自摘要)：本应用程序的总体目标 是对艾滋病痴呆症神经发病机制的重点检查 复合体(ADC)。他的实验设计依赖于使用小鼠模型 在神经退行性变中，Moloney小鼠的突变形式感染 白血病病毒(MoMuLV)诱导进行性神经免疫退行性变 与人类有一些临床和病理相似之处的疾病(NID) 免疫缺陷病毒1型(HIV1)相关中枢神经系统(CNS) 疾病。该模型与HIV-1感染中枢神经系统的相似性 包括：(1)选择性地消耗免疫系统中的T细胞和 中枢神经系统中的神经元；(2)中枢神经系统星形胶质细胞感染和过度激活 小胶质细胞；(3)病变中肿瘤坏死因子水平升高 (4)间接机制所致的神经元丢失。这个 本申请的具体目的是：(1)确定表达式 脑干、脊髓组织中肿瘤坏死因子、白介素1、Fas/FasL等细胞因子的水平 Ts1和WT感染小鼠和未感染小鼠的脊髓和大脑皮层 并对脑内产生的肿瘤坏死因子的浓度进行量化 Ts1感染小鼠不同时间点的脑干和大脑皮层 感染后；(2)确定中枢神经系统中哪些细胞类型表达肿瘤坏死因子， IL-1、Fas和FasL；哪些细胞类型发生凋亡；哪些细胞 在感染Ts1的小鼠中感染Ts1的类型；(3)为了确定是否有肿瘤坏死因子， IL-1和Fas信号转导是Ts1介导的信号转导途径 通过比较疾病进展和神经元丢失来实现神经退行性变 TS1感染的TNFR KO、TNF KO、IL-1R KO和Fas-以及FasL缺陷 分别与未感染的KO小鼠和感染Ts1的正常小鼠进行比较 并通过比较感染Ts1的小鼠的疾病进展和神经元丢失 FVB/N小鼠接受可溶性TNFR、可溶性Fas或可溶性IL-1R治疗；以及(4) 确定(A)肿瘤坏死因子和Fas或(B)肿瘤坏死因子和白介素1的联合作用 是预防双基因敲除(KO)小鼠疾病发展所必需的 纯合子对TNFR1和Fas的干扰以及在纯合子Fas小鼠中的作用 TNFR1和IL-1R的干扰。Ts1感染的综合治疗 同时具有可溶性肿瘤坏死因子和FasL受体或肿瘤坏死因子和白介素1受体的FVB/N小鼠将 也可以进行。

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.