MODELS OF AIDS DEMENTIA COMPLEX

艾滋病痴呆症模型

• 批准号: 2259725
• 负责人: JOHN R CORBOY
• 金额: $ 9.07万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2259725
• 关键词: AIDS dementia complex; HIV infections; animal breeding; astrocytes; beta galactosidase; cell type; encephalitis; experimental brain lesion; gene expression; genetic promoter element; genetically modified animals; glial fibrillary acidic protein; herpes simplex virus 1; human immunodeficiency virus 1; laboratory mouse; model design /development; neurons; nucleic acid repetitive sequence; opportunistic infections; pathologic process; southern blotting; tissue /cell culture; tumor necrosis factor alpha

The pathogenesis of HIV-1 infection in the central nervous system (CNS) is uncertain. The role of factors which regulate HIV-1 production in the brain or which actually cause damage to neural cells remains to be defined. Using transgenic mouse technology we will address several hypotheses relevant to the neuropathogenesis of HIV-1 in vivo including: 1. Inflammation in the brain activates HIV-1. Using an established line of transgenic mice in which beta-galactosidase (beta-gal) is expressed in the brain under the direction of HIV-1 long terminal repeat (LTR), we will create inflammation with a cerebral stab wound and herpes simplex virus type 1 encephalitis. beta-gal production will be compared in treated and untreated mice. 2. Tumor necrosis factor-alpha (TNF-alpha) is neurotoxic when secreted in the brain. We will generate transgenic mice which express TNF-alpha under the direction of a brain specific promoter, glial fibrillary acidic protein (GFAP), evaluate offspring mice neuropathologically, and compare the neuropathology to that seen in HIV-1 CNS infection. 3. HIV-1, transactivating protein (tat) is neurotoxic when secreted in the brain. We will create two sets of transgenic mice which express tat in the brain under the direction of GFAP and HIV-1 LTR, evaluate the offspring mice neuropathologically, and compare the neuropathology to that seen in HIV-1 CBS infection. 4. TNF-alpha and tat activate HIV-1 LTR in the brain. Transgenic mice expressing TNF-alpha and tat in the brain will be bred with HIV-1 LTR- beta-gal mice, and offspring carrying both transgenes will be assessed for beta-gal production in comparison to littermates who carry either one or neither transgene.

中枢神经系统（CNS）中HIV-1感染的发病机理为 不确定。 调节HIV-1产生在 大脑或实际对神经细胞造成损害的尚未 定义。 使用转基因鼠标技术，我们将解决几个 与HIV-1体内的神经病发生有关的假设包括： 1。大脑炎症激活HIV-1。 使用已建立的线路 β-半乳糖苷酶（β-gal）的转基因小鼠的表达 大脑在HIV-1长时间重复（LTR）的指导下，我们将 用大脑刺伤和单纯疱疹病毒产生炎症 1型脑炎。 将在经过处理的和 未经治疗的小鼠。 2。肿瘤坏死因子-Alpha（TNF-Alpha）是神经毒性的 大脑。 我们将生成在下面表达tnf-alpha的转基因小鼠 大脑特异性启动子的方向，神经胶质纤维酸性 蛋白质（GFAP），在神经病理学上评估后代小鼠，并比较 HIV-1 CNS感染中发现的神经病理学。 3。HIV-1，反式激活蛋白（TAT）是神经毒性的 脑。 我们将创建两组转基因小鼠，这些小鼠在 大脑在GFAP和HIV-1 LTR的指导下，评估 后代小鼠神经病理学，并将神经病理学比较 在HIV-1 CBS感染中可见。 4。TNF-Alpha和Tat激活大脑中的HIV-1 LTR。 转基因小鼠 在大脑中表达TNF-Alpha和TAT将用HIV-1 ltr-繁殖 将评估beta-gal小鼠和携带两个转基因的后代 与携带一个或一个的同窝同书相比，beta-gal的生产 都不是转基因。