Mechanisms of HAD:Role of CCL2 BBB & HIV Infection

HAD的机制：CCL2 BBB的作用

• 批准号: 8665484
• 负责人: Joan Weinberger Berman
• 金额: $ 37.58万
• 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/8665484
• 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）： 大脑在外周HIV感染后几天内被感染，尽管有cART，病毒仍然存在。CNS HIV感染通常导致HIV相关神经认知障碍或HAND的发展，其至少部分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。病毒进入大脑的一个主要机制是通过HIV感染的单核细胞和可能的T细胞穿过BBB的迁移。在非病理条件下，白细胞穿过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”）之间的特异性相互作用在白细胞渗出期间维持这些血管的不渗透性。然而，在NeuroAIDS的发病过程中，白细胞浸润到CNS中与BBB受损相关。因此，白细胞渗出穿过BBB中固有的分子相互作用被改变，导致BBB破坏增加。我们的数据表明，HIV感染的单核细胞和T细胞加上CCL 2作为一种化学引诱物，但不是其他趋化因子，导致增加这些细胞穿越血脑屏障的组织培养模型和破坏。我们证明，病毒以及CCL 2诱导的白细胞和脑微血管内皮细胞上的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CCL 2改变了它们的表达、定位、磷酸化和细胞连接蛋白的脱落，这些改变导致异常的白细胞/BBB细胞相互作用，导致增加的迁移和屏障破坏，有助于神经炎症和病毒损伤的特点NeuroAIDS这一更新是继续我们的研究机制的艾滋病毒感染的轮回细胞跨越BBB响应CCL 2，重点是一个特定的单核细胞群体，我们显示优先穿越BBB响应CCL 2，是非常容易受到HIV感染。我们将重点关注细胞连接分子PECAM-1，CD 99，JAM-A和ALCAM，作为参与单核细胞迁移失调和破坏BBB完整性的关键蛋白。我们还确定了其他蛋白质，可能有助于失调的轮回，以及单核细胞对艾滋病毒感染的易感性，我们将检查他们的表达和单核细胞的功能。我们将研究完整的和可溶性的连接蛋白的贡献，以增加transmigration，并确定路线，paracellular或transcellular，transmigration的未感染的和HIV单核细胞。我们将使用SIV模型证明这些过程的体内意义。