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：
8337731
负责人：
Joan Weinberger Berman
金额：
$ 37.56万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8337731
关键词：
AIDS neuropathy 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 Disease Endothelial Cells Exposure to Future Grant HIV HIV Infections Human Impairment In Vitro Individual Infection Infiltration Inflammation Intercellular Junctions Intervention Leukocyte Trafficking Leukocytes Life Mediating Membrane Modeling Neurocognitive 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 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）：外周 HIV 感染后数天内，大脑就会被感染，并且尽管进行了 cART，病毒仍然存在。 CNS HIV 感染通常会导致 HIV 相关神经认知障碍 (HAND) 的发生，这种疾病至少部分是由持续的神经炎症和导致 CNS 损伤的低水平病毒持续性介导的。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，白细胞跨 CNS 脉管系统的迁移不会破坏 BBB，因为白细胞和 BBB 细胞上的粘附分子、粘附连接和紧密连接蛋白（称为“细胞连接蛋白”）之间的特定相互作用维持了这些细胞的不渗透性。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 作为化学引诱剂，而不是其他趋化因子，会导致这些细胞在 BBB 组织培养模型中的迁移增加，并破坏该屏障。我们证明，病毒以及 CCL2 诱导白细胞和脑微血管内皮细胞上多种细胞连接蛋白的表达、加工和功能发生深刻变化。我们假设单核细胞的 HIV 感染和暴露于 CCL2 改变了它们的表达、定位、磷酸化和细胞连接蛋白的脱落，并且这些改变导致异常的白细胞/BBB 细胞相互作用，导致轮回和屏障破坏增加，导致神经炎症和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，重点是特定的我们展示的单核细胞群响应 CCL2 优先跨 BBB 迁移，并且非常容易受到 HIV 感染。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。