Mechanisms of HAD: Role of CCL2, BBB and HIV infection

HAD 的机制：CCL2、BBB 和 HIV 感染的作用

基本信息

批准号：
7195760
负责人：
Joan Weinberger Berman
金额：
$ 38.28万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-06 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7195760
关键词：
AIDS Dementia Complex AIDS neuropathy Acquired Immunodeficiency Syndrome Adaptor Signaling Protein Address Adherens Junction Adhesions Animal Model Astrocytes Binding Blood - brain barrier anatomy Blood Vessels Brain CC chemokine receptor 2 CCL2 gene Cell Adhesion Molecules Cell Communication Cell Count Cells Chemokine, Other Chemotactic Factors Complex Condition Cytoskeleton Data Dementia Detection Development Disruption Endothelial Cells Endothelium Event Goals HIV HIV Infections HIV encephalitis Highly Active Antiretroviral Therapy Individual Infiltration Inflammatory Intercellular Junctions Kinetics Leukocytes Lymphocyte Macaca Matrix Metalloproteinases Mediating Microglia Minocycline Modeling Neurologic Neurologic Dysfunctions Neurons Numbers Pathogenesis Peripheral Blood Mononuclear Cell Permeability Phenotype Process Property Proteins Role SIV Serum T-Lymphocyte Tight Junctions Time Time Study Viral Viral Load result antiretroviral therapy base macrophage migration monocyte monocyte chemoattractant protein 1 receptor novel protein expression research study response seal tissue culture

项目摘要

DESCRIPTION (provided by applicant): HIV infection of the CMS often results in the development of severe neurological complications, including HIV-associated dementia (HAD). The number of activated macrophages in the CMS appears to be a much better indicator of HAD than viral load, suggesting that leukocyte infiltration and dementia are tightly correlated. The process by which infected monocytes, and perhaps T cells, cross the blood brain barrier (BBB) and infiltrate the CMS is still not well understood. It is believed that under non-pathological conditions, the transmigration of leukocytes across the CMS vasculature does not disrupt the BBB because specific homophilic and heterophilic interactions between adhesion molecules, adherens junction and tight junction proteins (termed "cell junction proteins") on leukocytes and BBB cells maintain the impermeability of these vessels during leukocyte diapedesis. However, during the pathogenesis of HAD, leukocyte infiltration of the CMS is associated with BBB compromise. Thus the molecular interactions inherent in leukocyte diapedesis across the BBB are altered, resulting in increased BBB disruption. We have the novel finding that HIV-infected PBMC have an enhanced capacity to transmigrate across our tissue culture model of the BBB in response to CCL2, but not to other chemokines. This enhanced transmigration is associated with high expression of the CCL2 receptor, CCR2, and alterations in cell junction proteins in HIV-infected leukocytes. It is therefore our hypothesis that these alterations result in aberrant leukocyte/BBB cell interactions upon exposure of HIV-infected leukocytes to CCL2 during the process of transmigration, leading to enhanced migration and barrier disruption. To address this hypothesis we will; 1) analyze early events of HIV-infected PBMC transmigration and the kinetics of BBB disruption, 2) examine changes in matrix metalloproteinases (MMPs) and cell junction protein expression in BBB cells or HIV-infected PBMC after CCL2 treatment, 3) determine the contribution of cell junction proteins during the process of HIV- infected PBMC transmigration, 4) analyze complex formation between cell junction and intracellular adaptor proteins associated with junctional complex anchoring to the cytoskeleton during the process of HIV- infected PBMC transmigration, and 5) examine SIV infected macaques as an animal model of NeuroAIDS for the dynamic sequence of events that result in neurological dysfunction.

描述（由申请人提供）：CMS的HIV感染通常会导致严重神经系统并发症的发展，包括与HIV相关的痴呆症（HAT）。 CMS中活化的巨噬细胞的数量似乎比病毒载量更好，这表明白细胞浸润和痴呆密切相关。感染的单核细胞和T细胞的过程越过血脑屏障（BBB）并浸润CMS的过程尚不清楚。人们认为，在非病理条件下，跨CMS脉管系统的白细胞的迁移不会破坏BBB，因为特定的同质性和异质性相互作用在粘附分子之间，粘附连接和紧密连接蛋白之间的粘附分子和紧密连接蛋白（被称为“ be骨蛋白）在lukbbby细胞上保持不变的细胞”，这些蛋白质”是在lukbbb的范围内维持这些不足的细胞。二十。但是，在HAD发病机理期间，CMS的白细胞浸润与BBB妥协有关。因此，在整个BBB的白细胞尿症中固有的分子相互作用发生了变化，从而导致BBB的破坏增加。我们有一个新颖的发现，即感染HIV的PBMC具有增强的能力，可以响应CCL2而在BBB的组织培养模型中进行移民，但对其他趋化因子没有。这种增强的转移与CCL2受体，CCR2的高表达以及HIV感染的白细胞中细胞连接蛋白的变化有关。因此，我们的假设是，这些改变会导致白细胞/BBB细胞相互作用在移民过程中暴露于CCL2的HIV感染白细胞后，导致迁移和障碍破坏。为了解决这一假设，我们将； 1）分析HIV感染的PBMC转移和BBB破坏动力学的早期事件，2）检查基质金属蛋白酶（MMP）（MMP）和细胞连接蛋白在BBB细胞或HIV感染的PBMC中CCL2治疗后的PBMC中的细胞连接蛋白表达的变化，3）在CCL2处理后，3）确定pR的贡献。在HIV感染的PBMC转移过程中，细胞连接和细胞内适配器蛋白与连接型复合物相关的固定在细胞骨架上的形成，5）5）检查SIV感染的猕猴作为神经辅助的动物模型，以导致神经功能障碍的动态序列。