Cocaine-mediated neuroinflammation: Role in neuroAIDS

可卡因介导的神经炎症：在神经艾滋病中的作用

• 批准号: 8012440
• 负责人: Honghong Yao
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012440
• 关键词: AIDS Dementia Complex; AIDS neuropathy; Accounting; Acquired Immunodeficiency Syndrome; Address; American; Binding; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; CCL2 gene; Case Study; Cell Line; Cells; Central Nervous System Diseases; Cocaine; Cocaine Abuse; Complex; Development; Disease; Disease Progression; Drug abuse; Drug usage; Electrical Resistance; Endothelial Cells; Epidemic; Exhibits; HIV; HIV Infections; HIV encephalitis; HIV-1; Homeostasis; Human; Incidence; Individual; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory Response; Injection of therapeutic agent; Intervention; Lead; Leukocytes; Link; Macaca; Maintenance; Mediating; Mediator of activation protein; Microglia; Molecular; Monocyte Chemoattractant Protein-1; Mus; Needle Sharing; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Neuropathogenesis; Organ; Pathogenesis; Pathway interactions; Patients; Permeability; Play; Prevalence; Process; Property; Rattus; Regulation; Relative (related person); Reporting; Risk; Role; Route; SIV encephalitis; Signal Pathway; Source; Staging; Survival Rate; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; Transgenic Model; Up-Regulation; Viral Load result; Virus; Virus Replication; antiretroviral therapy; base; chemokine; cocaine exposure; cocaine receptor; drug abuser; efficacy testing; global health; in vitro Model; in vivo; innovation; intravenous drug use; macrophage; migration; monocyte; monocyte chemoattractant protein 1 receptor; nervous system disorder; neuroinflammation; neuropathology; novel; pathogen; prevent; public health relevance; response; sigma receptors; transmission process

DESCRIPTION (provided by applicant): It is becoming increasingly clear that HIV-1 infection and drug abuse are interlinked epidemics. In fact, cocaine, often abused by HIV-infected patients, has been suggested to hasten as well as worsen disease pathogenesis. HIV-1-associated neurological disorders (HAND) are primarily a result of increased influx of activated/infected monocytes from the periphery, in response to a chemokine gradient in the CNS. Among the known chemokines involved in this process, MCP-1 is known to correlate positively with HAND. Intriguingly, in our preliminary studies we have identified this chemokine as a key mediator that is up-regulated in both microglial cell line (BV-2) and in rat primary microglia that are exposed to cocaine. This effect is mediated through the cognate receptor for cocaine, the sigma receptor. We therefore hypothesized that cocaine-mediated enhancement of vascular changes in the CNS was involved in activation of sigma receptor leading to induction of MCP-1. To address this hypothesis two specific aims are proposed: 1) Investigate the molecular mechanisms involved in regulation of MCP-1 in microglia exposed to cocaine and, 2) Test the therapeutic potential of sigma receptor antagonist as an intervention strategy in vivo using the HIV Tat transgenic model of HIV neurodegeneration exposed to cocaine. These studies are both novel and innovative in that the efficacy of sigma receptor in abrogating monocyte migration can be of value not only for HAND but can be applicable to other neurodegenerative diseases as well. PUBLIC HEALTH RELEVANCE: HIV-1infected individuals that abuse cocaine have increased risk of vascular changes that can result in complications of the CNS. This study proposes to explore how cocaine abuse can lead to increased neuroinflammation, and subsequently, to develop therapeutic intervention to inhibit inflammation.

描述（由申请人提供）：越来越明显的是，HIV-1 感染和药物滥用是相互关联的流行病。事实上，经常被艾滋病毒感染者滥用的可卡因被认为会加速和恶化疾病的发病机制。 HIV-1 相关神经系统疾病 (HAND) 主要是由于中枢神经系统中趋化因子梯度的反应，激活/感染的单核细胞从外周流入增加的结果。在参与该过程的已知趋化因子中，MCP-1 与 HAND 呈正相关。有趣的是，在我们的初步研究中，我们已经确定这种趋化因子是一种关键介质，它在小胶质细胞系 (BV-2) 和暴露于可卡因的大鼠原代小胶质细胞中上调。这种作用是通过可卡因的同源受体（西格玛受体）介导的。因此，我们假设可卡因介导的中枢神经系统血管变化的增强参与了 σ 受体的激活，导致 MCP-1 的诱导。为了解决这一假设，提出了两个具体目标：1) 研究接触可卡因的小胶质细胞中 MCP-1 调节的分子机制，2) 使用 HIV Tat 测试 sigma 受体拮抗剂作为体内干预策略的治疗潜力暴露于可卡因的 HIV 神经变性转基因模型。这些研究既新颖又创新，因为西格玛受体在消除单核细胞迁移方面的功效不仅对 HAND 有价值，而且也适用于其他神经退行性疾病。 公共卫生相关性：滥用可卡因的 HIV-1 感染者会增加血管变化的风险，从而导致中枢神经系统并发症。这项研究旨在探索可卡因滥用如何导致神经炎症增加，并随后开发治疗干预措施来抑制炎症。