Cocaine & HIV: Role of PDGF/PDGF-Receptor Axis in Blood Brain Barrier Disruption

可卡因

• 批准号: 8267069
• 负责人: Shilpa J. Buch
• 金额: $ 36.58万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267069
• 关键词: AIDS Dementia Complex; Accounting; Acquired Immunodeficiency Syndrome; Adhesions; American; Binding; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Case Study; Cause of Death; Cells; Central Nervous System Diseases; Cocaine; Complex; Dementia; Development; Disease; Disease Progression; Drug usage; Electrical Resistance; Endothelial Cells; Exhibits; Goals; HIV; HIV Infections; HIV encephalitis; HIV-1; Homeostasis; Human; In Vitro; Incidence; Infection; Infiltration; Inflammatory Response; Injection of therapeutic agent; Intervention; Leukocytes; Link; Macaca; Maintenance; Mediating; Microarray Analysis; Microglia; Modeling; Molecular; Mononuclear; Mus; Nature; Needle Sharing; Nerve Degeneration; Neuroglia; Neurons; Nodule; Organ; PDGF inhibition; Pathogenesis; Patients; Permeability; Phagocytes; Phosphorylation; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor beta Receptor; Play; Prevalence; Process; Production; Property; Proteins; Proto-Oncogene Proteins c-sis; Rattus; Recreational Drugs; Role; Route; Source; Staging; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Tight Junctions; Transgenic Mice; Transgenic Organisms; Up-Regulation; Viral Load result; Virus; abstracting; base; cocaine exposure; exposed human population; global health; in vivo; inhibitor/antagonist; intravenous drug use; macrophage; monocyte; monolayer; nervous system disorder; neuropathology; neuroregulation; novel; novel therapeutics; pathogen; platelet-derived growth factor BB; prevent; receptor; simian human immunodeficiency virus; transmission process

Abstract IV drug use and HIV infections are two linked global health crises since needle sharing is a well-recognized mode of HIV transmission. While HIV-1 infection is the leading cause of death among Americans 25-44 years old, injection drug use now accounts for about one-third of all new US AIDS cases reported each year. Cocaine, often abused by HIV-infected patients, has been suggested to worsen HIV-associated dementia (HAD) via unknown mechanisms. The brain is a target organ for both, the recreational drugs and HIV-1. Disruption of the blood brain barrier (BBB) is the main route of HIV entry into the CNS. The mechanisms by which the monocytes and/or T cells cross the BBB into the CNS parenchyma still remain an enigma. BBB is critical for the maintenance of CNS homeostasis and for the regulation of the neural microenvironment. This proposal will investigate specific mechanisms by which cocaine and HIV co-operate to induce BBB disruption. We hypothesize that HIV proteins & cocaine can interact in an additive or synergistic manner to directly amplify cellular & molecular processes contributing to their toxic vascular effects such as, disruption of the BBB and increased transmigration of infected monocytes into the CNS. The rationale of this hypothesis is based on preliminary studies showing up-regulation of a vascular permeant PDGF-BB in the brains of macaques with Simian-human immunodeficiency virus encephalitis and in monocytes infected with HIV or exposed to cocaine. Reciprocally, our new findings also demonstrate that cocaine-mediated disruption of endothelial monolayer involves phosphorylation of the PDGF-beta receptor. This proposal will thus investigate a novel concept that PDGF/PDGF-R axis could be the missing link in cocaine/HIV-mediated disruption of BBB. Using a combination of in vitro and complementary murine models of HIV neurodegeneration, we will test the hypothesis in three specific aims: SA1 of the study will be focused on investigating the molecular mechanisms involved in upregulation of PDGF in monocytes exposed to HIV proteins and/or cocaine. SA2 will be focused on exploring the mechanisms involved in PDGF & cocaine-induced permeability changes in human brain microvascular endothelial cells. Finally, SA3 will use in vivo approach to test the hypothesis that inhibition of the PDGF/PDGF-R axis by the PDGF-beta receptor inhibitor gleevac, will result in abrogation of BBB disruption in HIV-transgenic rats and Tat transgenic mice exposed to cocaine.

摘要 静脉吸毒和艾滋病毒感染是两个相互关联的全球健康危机，因为共用针头是一个公认的问题。 艾滋病毒的传播方式。虽然HIV-1感染是25-44岁美国人死亡的主要原因， 在美国每年报告的艾滋病新病例中，注射毒品的使用占三分之一。 可卡因经常被艾滋病毒感染者滥用，被认为会加重艾滋病毒相关的痴呆症 (HAD)通过未知的机制。大脑是娱乐性毒品和HIV-1的靶器官。 血脑屏障（BBB）的破坏是HIV进入CNS的主要途径。的机制 单核细胞和/或T细胞是如何穿过血脑屏障进入中枢神经系统实质的仍是一个谜。BBB是 对于维持CNS稳态和调节神经微环境至关重要。 这项提案将调查可卡因和艾滋病毒合作诱导血脑屏障的具体机制 破坏我们假设HIV蛋白和可卡因可以以相加或协同的方式相互作用， 直接放大导致其毒性血管效应的细胞和分子过程，例如， 血脑屏障和感染的单核细胞向中枢神经系统的迁移增加。这一假设的基本原理是 基于初步的研究显示， 猴-人类免疫缺陷病毒脑炎和单核细胞感染HIV或 接触可卡因反过来，我们的新发现也表明，可卡因介导的干扰， 内皮细胞单层涉及PDGF-β受体的磷酸化。因此，本提案将调查 一个新的概念是，PDGF/PDGF-R轴可能是可卡因/HIV介导的BBB破坏中缺失的一环。 使用体外和互补的HIV神经变性小鼠模型的组合，我们将测试 假设在三个具体目标：SA 1的研究将集中在调查的分子机制 参与暴露于HIV蛋白和/或可卡因的单核细胞中PDGF的上调。SA 2将专注于 探索PDGF和可卡因诱导人脑通透性变化的机制 微血管内皮细胞最后，SA 3将使用体内方法来检验抑制 PDGF-β受体抑制剂格列伐克阻断PDGF/PDGF-R轴，将导致血脑屏障的消除 在暴露于可卡因的HIV转基因大鼠和达特转基因小鼠中，