HIV-ASSOCIATED CNS DYSFUNCTION IN PEDIATRIC AIDS

儿科艾滋病中与艾滋病毒相关的中枢神经系统功能障碍

• 批准号: 3099155
• 负责人: William D. Lyman
• 金额: $ 147.97万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-30 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3099155
• 关键词: AIDS; central nervous system disorders; child (0-11); embryo /fetus; human fetus tissue; human immunodeficiency virus 1; human tissue

The overall hypothesis to be tested in this proposal is that exposure of the human fetal central nervous system (CNS) to HIV-1 may be sufficient to cause the neurological dysfunction characteristic of pediatric AIDS. The basis for this assumption is that a significant number of children with AIDS and others without clinical signs of disease but with congenital HIV-1 infection exhibit cognitive, behavioral, and neurodevelopmental abnormalities. Significant neuropathologic changes in the CNS of children and fetuses infected by HIV-1 but without other signs of AIDS have also been noted. Furthermore, HIV-1 nucleic acid sequences or proteins and signs of productive viral infection have been observed in the affected tissues and studies in vitro have demonstrated HIV-1 infection of glial cells. To define the role of HIV-1 in pediatric AIDS more precisely, a group of neuroscientists, each expert in a different neural cell type, has come together to pursue this question using a combination of morphologic, biochemical an molecular biologic techniques. Because of alterations in normal cognitive development in HIV-1 infected children, Project 1 will study the effect of HIV-1 on neuronal differentiation with a focus on specific neurotransmitter systems and on neuronal cytoskeletal components. Project 2 will complement Project 1 in that it will focus primarily on the astrocyte cytoskeleton and metabolic function in HIV-1 infection because of the reactive astrocytosis described in pediatric AIDS and the ability of astrocytes to elicit cytokines which may modulate CNS function. Project 3 will focus on microglia in the fetal CNS because this cell type is believed to be pivotal in AIDS neuropathology. This project will examine HIV-1 infection of microglia in vivo and in vitro and examine the role of cytokines in tissue damage. Because myelin pathology is prominent in pediatric AIDS, Project 4 will examine myelinogenesis and dysmyelination in the human fetal CNS exposed to HIV-1 in vivo. Project will also investigate the mechanisms related to myelin biology using dissociated cell culture and organotypic explant cultures. Project 5 focuses on the involvement of endothelial cells in the pathophysiology of CNS disease because evidence indicates that endothelial cells may be infected by HIV-1 and they provide the first barrier to viral entry into the CNS. Additionally, endothelial cells produce cytokines which may be involved in the pathophysiology of AIDS. Lastly, Project 6 will use an in vitro neuronal cell model to explore the interaction of HIV-1 genes on host cell gene expression and converse, host cell control over HIV-1 gene expression. The studies proposed in this Program Project application should answer many of the pressing questions related to nervous system disease in pediatric AIDS. Among these questions are the determination of a direct neurotropism of HIV-1; factors that are involved in the neuroinvasiveness of this virus; and, mechanisms of HIV neurovirulence. These studies may suggest new strategies to prevent or treat more effectively neurologic disease in pediatric AIDS.

本提案中要检验的总体假设是， 人胎儿中枢神经系统（CNS）对HIV-1的敏感性可能足以 会导致儿童艾滋病的神经功能障碍 的 这一假设的基础是，大量的儿童， 艾滋病和其他没有疾病临床症状但先天性HIV-1的人 感染表现为认知、行为和神经发育 异常 儿童中枢神经系统的显著神经病理学变化 感染HIV-1但没有其他艾滋病迹象的胎儿也 被注意到了。 此外，HIV-1核酸序列或蛋白质和 在受影响的人中观察到生产性病毒感染的迹象， 组织和体外研究表明，HIV-1感染的神经胶质细胞 细胞 为了更准确地定义HIV-1在儿科艾滋病中的作用， 一组神经科学家，每个专家在不同的神经细胞类型， 一起来研究这个问题，使用形态学， 生物化学和分子生物学技术。 由于改变， HIV-1感染儿童的正常认知发育，项目1将 研究HIV-1对神经元分化的影响，重点是 特异性神经递质系统和神经元细胞骨架成分。 项目2将补充项目1，因为它将主要侧重于 星形胶质细胞细胞骨架和代谢功能，因为 在儿童艾滋病中描述的反应性星形细胞增多症， 星形胶质细胞以引发可调节CNS功能的细胞因子。 项目3 将集中在胎儿中枢神经系统中的小胶质细胞，因为这种细胞类型被认为是 在艾滋病的神经病理学中至关重要。 该项目将研究HIV-1 感染的小胶质细胞在体内和体外，并检查的作用， 细胞因子在组织损伤中的作用 因为髓磷脂病理学在 项目4将研究儿童艾滋病的髓鞘生成和髓鞘形成障碍， 体内暴露于HIV-1的人胎儿CNS。 项目还将 用分离的细胞研究髓鞘生物学的相关机制 培养和器官型外植体培养。 项目5的重点是 内皮细胞参与中枢神经系统疾病的病理生理 因为有证据表明内皮细胞可能被HIV-1感染， 它们是病毒进入中枢神经系统的第一道屏障。 此外，内皮细胞产生细胞因子，其可能参与 艾滋病的病理生理学 最后，项目6将使用体外 神经元细胞模型研究HIV-1基因与宿主细胞的相互作用 基因表达和相反，宿主细胞控制HIV-1基因表达。 本计划项目申请中提出的研究应该回答许多问题 儿童神经系统疾病相关的紧迫问题 艾滋病 在这些问题中，有一个是确定一个直接的亲神经性 HIV-1;与这种病毒的神经侵袭性有关的因素; 以及HIV神经毒力的机制。 这些研究可能表明新的 更有效地预防或治疗神经系统疾病的策略 儿科艾滋病