Mechanisms of HAD:Role of CCL2 BBB & HIV Infection

HAD的机制：CCL2 BBB的作用

基本信息

批准号：
8848884
负责人：
Joan Weinberger Berman
金额：
$ 9.03万
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 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848884
关键词：
ALCAM gene Acquired Immunodeficiency Syndrome Adaptor Signaling Protein Address Adherens Junction Aftercare Binding Brain CCL2 gene CD31 Antigens Cell Adhesion Molecules Cell Communication Cell model Cells Chemotactic Factors Cultured Cells Data Development Endothelial Cells Exposure to Future Grant HIV HIV Infections HIV-associated neurocognitive disorder Human Impairment In Vitro Individual Infection Infiltration Inflammation Intercellular Junctions Intervention Leukocyte Trafficking Leukocytes Life Mediating Membrane Modeling Pathogenesis Peripheral Peripheral Blood Mononuclear Cell Phenotype Phosphorylation Population Predisposition Prevalence Principal Investigator Process Proteins Regulation Role Route SIV Serum Signal Transduction T-Lymphocyte Testing Tight Junctions Tissues Viral Virus Virus Diseases antiretroviral therapy cadherin 5 chemokine global health in vivo monocyte neuroAIDS neuroinflammation novel programs protein expression response success tissue culture

项目摘要

DESCRIPTION (provided by applicant): The brain becomes infected within days after peripheral HIV infection and viral presence persists despite cART. CNS HIV infection often results in the development of HIV Associated Neurocognitive Disorders, or HAND, that are mediated, at least in part, by ongoing neuroinflammation and low level viral persistence that cause CNS damage. A major mechanism by which virus enters the brain is by the transmigration of HIV-infected monocytes and perhaps T cells across the BBB. Under non-pathological conditions, the transmigration of leukocytes across the CNS vasculature does not disrupt the BBB because specific 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 NeuroAIDS, leukocyte infiltration into the CNS is associated with BBB compromise. Thus the molecular interactions inherent in leukocyte diapedesis across the BBB are altered, resulting in increased BBB disruption. Our data indicate that HIV infection of monocytes and T cells plus CCL2 as a chemoattractant, but not other chemokines, cause increased transmigration of these cells across a tissue culture model of the BBB and disruption of that barrier. We demonstrated that the virus as well CCL2 induced profound changes in expression, processing and function of diverse cell junction proteins on both leukocytes and brain microvascular endothelial cells. We hypothesize that HIV infection of monocytes and exposure to CCL2 alter their expression, localization, phosphorylation and shedding of cell junction proteins and that these alterations result in aberrant leukocyte/BBB cell interactions, leading to increased transmigration and barrier disruption, contributing to the neuroinflammation and viral damage that characterize NeuroAIDS This renewal is to continue our studies of the mechanisms of transmigration of HIV infected cells across the BBB in response to CCL2, with emphasis on a specific monocyte population that we showed preferentially transmigrates across the BBB in response to CCL2 and is highly susceptible to HIV infection. We will focus on the cell junction molecules PECAM-1, CD99, JAM-A, and ALCAM, as critical proteins involved in dysregulation of monocyte transmigration and disruption of BBB integrity. We also identified additional proteins that may facilitate dysregulated transmigration as well as monocyte susceptibility to HIV infection, and we will examine their expression and function on monocytes. We will examine the contribution of intact and soluble junction proteins to increased transmigration, and determine the route, paracellular or transcellular, of transmigration of uninfected and HIV monocytes. We will demonstrate the in vivo significance of these processes using an SIV model.

描述（由申请人提供）：大脑在周围HIV感染后的几天内被感染，尽管卡车，病毒存在仍然存在。 CNS HIV感染通常会导致与HIV相关的神经认知障碍或手的发展，这些神经认知障碍至少部分通过持续的神经炎症和低水平的病毒持久性介导，从而造成CNS损害。病毒进入大脑的一个主要机制是感染 HIV 的单核细胞以及可能还有 T 细胞穿过 BBB 的迁移。在非病理条件下，白细胞在CNS脉管系统中的移民不会破坏BBB，因为粘附分子之间的特定相互作用，粘附连接和紧密连接蛋白（称为“细胞连接蛋白”）（称为“细胞连接蛋白”）在白细胞和BBB细胞上维护白细胞渗出期间的血管。然而，在 NeuroAIDS 发病过程中，白细胞浸润中枢神经系统与血脑屏障受损有关。因此，跨 BBB 的白细胞渗出所固有的分子相互作用发生改变，导致 BBB 破坏增加。我们的数据表明，单核细胞和T细胞的HIV感染加上CCL2作为趋化剂，但没有其他趋化因子，但没有导致这些细胞在BBB的组织培养模型中增加了这些细胞的迁移和该障碍的破坏。我们证明了该病毒和CCL2也引起了白细胞和脑微血管内皮细胞上各种细胞连接蛋白的表达，处理和功能的深刻变化。我们假设单核细胞的HIV感染和暴露于CCL2改变了其表达，定位，磷酸化和细胞连接蛋白的脱落，并且这些改变导致白细胞/BBB细胞相互作用异常，从而导致跨移术和障碍的增加，导致神经衰减，从而导致神经膜化症状，从而增加。 NeuroAIDS 的病毒损伤特征本次更新是为了继续研究 HIV 感染细胞响应 CCL2 跨 BBB 迁移的机制，重点是特定的我们表现出的单核细胞群体优先响应CCL2，并且非常容易受到HIV感染的影响。我们将重点关注细胞连接分子 PECAM-1、CD99、JAM-A 和 ALCAM，它们是参与单核细胞迁移失调和 BBB 完整性破坏的关键蛋白质。我们还鉴定了可能促进轮回失调以及单核细胞对 HIV 感染的易感性的其他蛋白质，我们将检查它们在单核细胞上的表达和功能。我们将检查完整的可溶性连接蛋白对增加迁移的贡献，并确定未感染和 HIV 单核细胞的迁移途径（旁细胞或跨细胞）。我们将使用 SIV 模型展示这些过程的体内重要性。