EXTENSION OF MERIT AWARD 1 R37 MH 46815 04

延长优异奖 1 R37 MH 46815 04

• 批准号: 2674983
• 负责人: William D. Lyman
• 金额: $ 27.44万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2674983
• 关键词: AIDS; HIV infections; astrocytes; cell differentiation; cellular pathology; congenital infection; encephalitis; female; gestational age; human fetus tissue; human immunodeficiency virus 1; human tissue; microglia; nervous system infection; neurons; neurotropic virus; oligodendroglia; organ culture; polymerase chain reaction; virus classification

The hypothesis to be tested in this proposal is that different human immunodeficiency virus-1 (HIV-1) isolates vary in their neural system (CNS) organotypic tissue culture model. Additionally, because these variations may be reflected in vivo by the spectrum of neuropathologic changes associated with acquired immunodeficiency syndrome (AIDS), experiments will be conducted to explore the correlation between in vitro and in vivo pathologic changes. Neurologic dysfunction is a common, sometimes initial and diagnostic, finding in AIDS. In adult AIDS, the relationship between HIV-1 nd neuropathology remains unclear but, however, in pediatric AIDS this proposed direct relationship between virus and pathology is less controversial. The evidence to support a causal relationship between HIV-1 and the neuropathology of pediatric AIDS stems from clinical observations of children born with congenital HIV-1 infection and pathologic studies which surveyed pediatric and human fetal brains using immunocytochemical and nucleic acid techniques in combination with light and electron microscopy. Because these neural environments are more pristine than adult brains of AIDS patients, a more directly related association between HIV-1 and nervous system pathology emerged. In pediatric brain and spinal cord an array of changes were observed which ranges from subacute encephalitic to CNS vasculopathy to axon and myelinopathy. A similarly diverse picture is emerging in studies, in our laboratories, on HIV-1 related neuropathology in fetal brain. Because recently, opinion has developed that HIV-1 may exhibit different cellular tropisms, the most common of which are the lymphocytotrophicc (L) and monocytotrophic (M) isolates; this study was conceived so as to explore this question using a recently developed tissue culture model of human fetal CNS tissue maintained in organotypic culture. Cells in this culture system develop and differentiate into neurons forming synapses, astrocytes, oligodendtocytes, microglia and vascular endothelia which express cell-type specific markers. Preliminary studies have shown that the IIIb and RF2 laboratory isolates of HIV-1 can induce morphologic changes in well- differentiated cultures similar to changes observed in vivo. Therefore, this proposal will further explore and define the ability of HIV-1 to either directly or indirectly cause CNS pathology. Such insights may permit the design of improved preventative or therapeutic protocols for combatting HIV infection.

这项提议要检验的假设是，不同的人类 免疫缺陷病毒-1(HIV-1)分离株的神经系统(CNS)不同 器官型组织培养模型。此外，因为这些变种 可能在体内通过神经病理变化的光谱反映出来 与获得性免疫缺陷综合症(AIDS)相关的实验将 以探索体外和体内的相关性 病理改变。神经功能障碍是一种常见的，有时是最初的 以及对艾滋病的诊断和发现。在成人艾滋病中，两者的关系 HIV-1神经病理学尚不清楚，但在儿童艾滋病中 这种提出的病毒和病理之间的直接关系较少 有争议的。支持因果关系的证据 HIV-1与儿童艾滋病干神经病理的关系 先天性HIV-1感染患儿的临床观察 以及对儿童和人类胎儿大脑进行的病理学研究 使用免疫细胞化学和核酸技术结合 光学显微镜和电子显微镜。因为这些神经环境 艾滋病患者比成人大脑更原始，有更直接的关系 HIV-1与神经系统病理之间的联系出现了。在……里面 观察了儿童脑和脊髓的一系列变化， 范围从亚急性脑炎到中枢神经系统血管病变再到轴突和 髓鞘病。在研究中也出现了类似的不同图景，在我们的 实验室对胎儿大脑中HIV-1相关的神经病理进行了研究。因为 最近，有观点认为，HIV-1可能表现出不同的细胞 嗜性，其中最常见的是淋巴细胞营养性(L)和 单核细胞营养性(M)分离株；本研究旨在探索 这个问题使用了最近开发的人类组织培养模型 器官培养中维持的胎儿中枢神经系统组织。此培养物中的细胞 系统发育并分化为神经元，形成突触，星形胶质细胞， 表达细胞型的少突胶质细胞、小胶质细胞和血管内皮细胞 特定的标记。初步研究表明，IIIb和RF2 HIV-1实验室分离株可诱导井下组织发生形态变化 与体内观察到的变化相似的分化培养。因此， 这项提案将进一步探索和定义艾滋病毒-1 可直接或间接引起中枢神经系统病理改变。这样的见解可能会 允许设计改进的预防或治疗方案 抗击艾滋病毒感染。