BLOOD BRAIN BARRIER AND SIV ENCEPHALITIS

血脑屏障和 SIV 脑炎

• 批准号: 2853182
• 负责人: JOSEPH L MANKOWSKI
• 金额: $ 8.28万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2001-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2853182
• 关键词: AIDS dementia complex; Macaca mulatta; astrocytes; blood brain barrier; cell adhesion molecules; immunocytochemistry; in situ hybridization; infectious encephalitis; macrophage; pathologic process; polymerase chain reaction; simian immunodeficiency virus; virus protein; western blottings

DESCRIPTION: This is an amended KO1 application requesting five years of support to provide research training by using an SIV macaque animal model to study the role of the BBB in the development of encephalitis and AIDS dementia. The candidate's preliminary data have demonstrated that neurovirulent but not non-neurovirulent strains of SIV productively infect brain microvessel EC both in vivo and in vitro. This result suggests that the neuroendothelial cells may play an important role in the pathogenesis of SIV encephalitis, and that compromise of CNS EC function may play a pivotal role in BBB disturbances. Furthermore, infection of EC, and alterations in the EC expression of cell adhesion molecules (CAMs) may also contribute to a loss of BBB integrity. The central hypothesis of this application is that BBB dysfunction plays a crucial role in the development of encephalitis and AIDS-related dementia. The first Specific Aim of this application is to assess BBB integrity during acute, latent, and chronic stages of SIV infection to determine whether loss of BBB function is associated with CNS viral load, and CNS pathology. The second Specific Aim is to examine the dynamics of EC infection during disease progression in order to determine if EC infection is associated with altered BBB integrity, increased CNS viral load, and CNS pathology. For both Aims 1 and 2, in vivo analysis employing immunohistochemistry, in situ hybridization, and reverse transcriptase polymerase chain reaction (RT-PCR) done in situ, will be performed on CNS tissues from animals at various stages of disease. CNS microvessel isolation will permit further characterization of BBB integrity and EC infectivity. The third Specific Aim is to determine if CAMs mediate the interaction between EC and infected and uninfected peripheral blood lymphocytes and monocyte/macrophages during disease progression. Adhesion will be examined both in vivo and in vitro to define the functional role of CAMs during disease progression. Overall, these studies are intended to contribute to the understanding of the role the BBB plays in the development of lentiviral encephalitis.

描述：这是一项修订的KO1申请，要求五年 支持通过使用SIV猕猴模型来提供研究培训 研究BBB在脑炎和艾滋病发展中的作用 失智。 候选人的初步数据表明 神经毒动，但不是非神经脊髓性的SIV菌株有效感染 脑微血管EC在体内和体外均具有。 这个结果表明 神经内皮细胞可能在 SIV脑炎，以及CNS EC功能的妥协可能起关键 在BBB干扰中的作用。 此外，EC感染和改变 细胞粘附分子（CAM）的EC表达也可能有助于 BBB完整性的丧失。 该应用程序的中心假设是 BBB功能障碍在脑炎的发展中起着至关重要的作用 艾滋病相关的痴呆症。 该应用程序的第一个具体目的是 评估SIV的急性，潜在和慢性阶段期间的BBB完整性 感染以确定BBB功能是否与CN相关 病毒负荷和CNS病理学。 第二个具体目的是检查 疾病进展过程中EC感染的动力学，以确定是否是否 EC感染与BBB完整性的改变有关，CNS病毒增加 负载和CNS病理学。 对于两个目标1和2，使用体内分析 免疫组织化学，原位杂交和逆转录酶 聚合酶链反应（RT-PCR）原位将在CNS上进行 来自疾病各个阶段的动物的组织。 中枢神经系统 隔离将允许进一​​步表征BBB完整性和EC 感染力。 第三个具体目的是确定凸轮是否介导 EC与受感染和未感染的外周血之间的相互作用 疾病进展过程中淋巴细胞和单核细胞/巨噬细胞。 粘附 将在体内和体外检查以定义的功能作用 疾病进展过程中的凸轮。 总体而言，这些研究旨在 有助于理解BBB在发展中所扮演的角色 慢病毒脑炎。