BBB Tight Junctions During HIV-1 dementia

HIV-1 痴呆期间的 BBB 紧密连接

• 批准号: 7050162
• 负责人: Yuri Persidsky
• 金额: $ 28.6万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050162
• 关键词: AIDS dementia complex; G protein; NOD mouse; SCID mouse; antigen antibody reaction; astrocytes; blood brain barrier; cell cell interaction; cell migration; confocal scanning microscopy; digital imaging; electron microscopy; encephalitis; flow cytometry; human immunodeficiency virus 1; human tissue; immunocytochemistry; immunofluorescence technique; mixed tissue /cell culture; monocyte; tight junctions; western blottings

DESCRIPTION (provided by applicant): It is generally agreed that the blood-brain barrier (BBB) is impaired in HIV-1 associated dementia (HAD). However, the mechanism for BBB dysfunction is not well understood. Post-mortem examination of brain tissue from subjects with HIV-1 encephalitis (HIVE) revealed that brain microvascular endothelial cell (BMVEC) tight junction (TJ) integrity is diminished and can be correlated with macrophage egress and HAD. How immune competent HIV-1 -infected macrophages influence BMVEC TJ expression and function resulting in BBB compromise is the focus of the proposal. To address this, we asked the following questions: 1) Do immune- activated and/or virus-infected monocytes affect BMVEC TJ assembly? 2) Can modulation of key signaling pathways (such as Rho) for regulation of cytoskeletal organization in BMVEC alter TJ function? 3) Can inhibition of Rho prevent monocyte migration into brain during HIVE? We will employ (a) primary cell models, (b) a functional BBB model consisting of BMVEC and astrocytes seeded on opposing sides of a porous membrane, and (c) a novel xenograft system for HIVE in which peripheral human peripheral blood lymphocytes and monocytes have been shown to migrate into brain parenchyma. These will provide clues about how TJ integrity may be manipulated pharmacologically. Such studies should have broad relevance in the pathogenesis of a wide range of neurodegenerative disorders.

描述（由申请人提供）：通常同意 HIV-1相关痴呆（HAD）中血脑屏障（BBB）受损。 但是，BBB功能障碍的机制尚不清楚。验尸 检查HIV-1脑炎受试者（HIVE）的脑组织检查 发现脑微血管内皮细胞（BMVEC）紧密连接（TJ） 完整性会降低，并且可以与巨噬细胞出口相关。 免疫胜任HIV -1感染的巨噬细胞如何影响BMVEC TJ表达 导致BBB妥协的功能是该提案的重点。到 解决这个问题，我们提出了以下问题：1）进行免疫激活和/或 病毒感染的单核细胞会影响BMVEC TJ组装？ 2）可以调节钥匙 信号通路（例如RHO）用于调节细胞骨架组织 BMVEC Alter TJ功能？ 3）可以抑制RHO预防单核细胞迁移 蜂巢期间进入大脑？我们将采用（a）主电池模型，（b）a 由BMVEC和星形胶质细胞组成的功能性BBB模型在相对 多孔膜的侧面，以及（c）一种新型的异种移植系统，用于其中 周围人类外周血淋巴细胞和单核细胞已显示为 迁移到大脑实质中。这些将提供有关TJ完整性的线索 可以通过药理学进行操纵。这样的研究应该具有广泛的意义 在广泛的神经退行性疾病的发病机理中。