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BRAIN AND SPINAL CORD DISEASE IN HIV INFECTION

HIV 感染引起的脑部和脊髓疾病

基本信息

批准号：
2669000
负责人：
CAROL K PETITO
金额：
$ 26.48万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-04-01 至 1999-02-28
项目状态：
已结题

项目摘要

Human immunodeficiency-virus(HIV) encephalitis and vacuolar myelopathy (VM) are among the most common diseases of the brain and spinal cord in patients with the acquired immunodeficiency syndrome (AIDS). However, the mechanisms by which CNS injury occurs in these two disorders are incompletely understood. Although HIV encephalitis (HIVE) correlates well with brain atrophy and with AIDS dementia, atrophy and dementia is not always accompanied by HIV. Vascular myelopathy (VM), the most common cause of myelopathies in AIDS, is clearly associated with HIVE, yet a number of studies, including our own, indicate that it is not due to a direct HIV myelitis. The work completed during the current funding period highlights three potential mechanisms that may be important: a chronically-opened blood brain barrier (BBB) in the cerebral white matter; the identification of programmed cell death (apoptosis) in the cerebral grey matter; a close association between VM and HIVE. The following hypotheses and specific aims will further explore these mechanisms. 1. The diffuse white matter changes in brains of HIV- infected patients are due to a chronically-opened blood-brain barrier. 2 The BBB breakdown is due to and follows endothelial activation and occurs through vesicular transport in cerebral venules. 3. Diffuse white matter changes in brains of HIV-infected patients are secondary to a chronically-opened blood-brain barrier rather than by direct HIV infection. 4. The neuronal loss in AIDS brains is due to programmed cell death (apoptosis), mediated via activated, HIV-infected microglia and is the cause of AIDS dementia. 5. The etiology of VM is multifactorial and includes vitamin B12 deficiency as well as by indirect effects of HIV encephalitis. These hypotheses will be examined in brains of AIDS patients with or without HIVE and VM and in a nude mouse model of TNF toxicity induced by intramuscular or intracerebral inoculations of a TNF-producing tumor cell line. Techniques to be used include immunohistochemistry, in situ end labeling of DNA fragments, light and electron microscopy and BBB tracer and transport studies. The results of the proposed projects will clarify the cellular mechanisms whereby brain and spinal cord damage occur in HIV infection, establish the etiology of VM and offer the potential for therapeutic interventions of TNF-induced BBB breakdown or tissue damage, apoptosis or vitamin deficiency.

人类免疫缺陷病毒（HIV）脑炎和空泡性脊髓病 (VM)是最常见的脑和脊髓疾病之一，获得性免疫缺陷综合征（AIDS）患者。然而，在这方面，在这两种疾病中发生CNS损伤的机制是不完全理解。虽然HIV脑炎（HIVE）与以及脑萎缩和艾滋病痴呆，萎缩和痴呆，并不总是伴随着艾滋病毒。血管性脊髓病（VM），最常见的艾滋病脊髓病变的原因，显然与荨麻疹有关，但许多研究，包括我们自己的研究，表明这不是由于直接感染艾滋病病毒。本次资助期间完成的工作本报告所述期间突出强调了三个可能重要的潜在机制：脑白色区血脑屏障（BBB）慢性开放程序性细胞死亡（凋亡）的鉴定脑灰质; VM和HIVE之间的密切联系。的下面的假设和具体目标将进一步探讨这些机制等 1. HIV感染者脑内弥漫性白色改变受感染的患者是由于长期开放的血脑屏障。 2.血脑屏障的破坏是由于内皮细胞的激活，通过脑小静脉中的囊泡运输发生。 3. 弥漫性 HIV感染者大脑中的白色物质变化是继发于一个慢性开放的血脑屏障，而不是直接的艾滋病毒感染 4. 艾滋病大脑中的神经元损失是由于程序化的细胞死亡（凋亡），通过激活的HIV感染的小胶质细胞介导也是艾滋病痴呆的原因 5. VM的病因是多因素，包括维生素B12缺乏以及间接艾滋病毒脑炎的影响。这些假设将在大脑中进行检验艾滋病患者有或没有HIVE和VM和裸鼠模型肌内或脑内接种诱导的TNF毒性一种产生肿瘤坏死因子的肿瘤细胞系将使用的技术包括免疫组化、DNA片段原位末端标记、光和电子显微镜和BBB示踪剂和运输研究。结果的拟议项目将澄清细胞机制，脑和脊髓损伤发生在艾滋病毒感染，建立 VM的病因学，并提供治疗干预的潜力， TNF诱导的BBB破坏或组织损伤、细胞凋亡或维生素缺陷