Mechanisms of HAD:Role of CCL2 BBB & HIV Infection

HAD的机制：CCL2 BBB的作用

• 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
• 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

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)： 在外周HIV感染后的几天内，大脑会受到感染，尽管CART，病毒的存在仍然存在。中枢神经系统HIV感染通常导致HIV相关神经认知障碍或手的发展，至少部分是由持续的神经炎症和低水平的病毒持续导致中枢神经系统损害所介导的。病毒进入大脑的一个主要机制是艾滋病毒感染的单核细胞和T细胞跨血脑屏障的轮回。在非病理条件下，白细胞跨中枢血管系统的迁移不会破坏血脑屏障，因为白细胞和血脑屏障细胞上的黏附分子、黏附连接和紧密连接蛋白(称为细胞连接蛋白)之间的特异性相互作用维持了这些血管在白细胞分裂过程中的不通透性。然而，在神经艾滋病的发病机制中，白细胞渗入中枢神经系统与血脑屏障受损有关。因此，跨越血脑屏障的白细胞滞留所固有的分子相互作用被改变，导致血脑屏障破坏增加。我们的数据表明，单核细胞和T细胞加上CCL2作为趋化剂而不是其他趋化因子的HIV感染，会导致这些细胞跨血脑屏障组织培养模型的迁移增加，并破坏这一屏障。我们证明了病毒和CCL2诱导了白细胞和脑微血管内皮细胞上不同细胞连接蛋白的表达、加工和功能的深刻变化。我们假设，HIV感染单核细胞和暴露于CCL2会改变它们的表达、定位、磷酸化和细胞连接蛋白的脱落，这些变化导致白细胞/BBB细胞相互作用异常，导致移行和屏障破坏，导致神经性艾滋病的神经炎症和病毒损伤。这一更新是为了继续我们的研究，即HIV感染细胞响应CCL2跨血脑屏障迁移的机制，重点是我们显示的特定的单核细胞群体，我们显示出对CCL2的反应优先跨BBB迁移，并且对HIV感染高度敏感。我们将重点介绍细胞连接分子PECAM-1、CD99、JAM-A和alcam，它们是参与单核细胞迁移失调和破坏血脑屏障完整性的关键蛋白。我们还鉴定了可能促进异常转运以及单核细胞对HIV感染的易感性的其他蛋白质，并将检测它们在单核细胞上的表达和功能。我们将研究完整的和可溶的连接蛋白对增加移行的贡献，并确定未感染的单核细胞和HIV单核细胞移行的途径，无论是细胞旁的还是跨细胞的。我们将使用SIV模型演示这些过程的活体意义。