Opioid Modulation of Inflammatory Monocyte Activity Involved in HIV Susceptibilit

阿片类药物对与 HIV 易感性相关的炎症单核细胞活性的调节

• 批准号: 8268445
• 负责人: Thomas J Rogers
• 金额: $ 28.81万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268445
• 关键词: Acute; Address; Agonist; Alkaloids; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Applications Grants; Biochemical; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; CCL2 gene; CCR5 gene; CXCR4 gene; Cells; Chemokine (C-C Motif) Receptor 5; Clinical Research; Country; Dementia; Depressed mood; Development; Disease; Dynorphins; Elements; Exhibits; Grant; HIV; HIV encephalitis; HIV-1; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Intravenous; Laboratories; Leucocytic infiltrate; Maps; Mediator of activation protein; Mesylates; Microglia; Modeling; Molecular; Molecular Cloning; Morphine; Nature; Neuraxis; Opioid; Opioid Peptide; Opioid Receptor; Pharmaceutical Preparations; Phase; Phenotype; Physiological Processes; Predisposition; Process; Production; Promoter Regions; Reporting; Research; SIV; Signal Transduction; Surface; T-Lymphocyte; Therapeutic; Transcriptional Regulation; Translational Research; Viral; Viral Encephalitis; Virus; Virus Diseases; alanylglycine; base; chemokine; chemokine receptor; drug abuser; drug of abuse; glycylphenylalanine; inflammatory modulation; macrophage; migration; monocyte; nervous system disorder; neuropathology; peripheral blood; promoter; receptor expression; research and development; trafficking; transmission process

Recent research has suggested that opioid administration alters susceptibility to a variety of infectious agents, including the Human Immunodeficiency Virus (HIV). It is estimated that a third of HIV-infected individuals in this country are intravenous opioid drug abuser. Little is known, however, about the influence of opioid drugs of abuse on HIV infection of the central nervous system (CNS), or associated neurological disorders including dementia. Current evidence indicates that initial transmission of the virus to the CNS involves trafficking of infected blood-derived monocytes during the acute phase of the infection. The traffic of monocytes to the CNS is a normal physiological process, but is augmented during inflammation and/or in association with infection of the brain. Evidence reported from our laboratory, as well as others, suggest that opioid drugs may promote the trafficking process that leads to migration of infected cells to the brain. Our hypothesis in this application is that opioids have a significant ability to alter the development of HIV encephalitis by altering the expression of critical chemokines and chemokine receptors. We believe that the opioid administration promotes the development of pro-inflammatory monocytes which possess an elevated capacity to both produce and respond to pro-inflammatory chemokines, and by virtue of greater trafficking capacity, accelerate the transit of virally infected cells into the brain. In this grant project, we will examine the effect of opioid administration on development of a proinflammatory monocyte phenotype. We will determine the molecular mechanism for mu and kappa opioid effects on the expression of the critical chemokine receptor CCR2, as well as the very important pro-inflammtory chemokine MCP-1. Our laboratory has shown that acute mu opioid administration induces the expression of the chemokine receptors CCR5 and CXCR4. We will extend these studies to determine the biochemical basis for these effects using cloned molecular constructs for the CCR2 and MCP-1 promoters. In contrast, our results suggest that kappa opioids inhibit HIV-1 coreceptor expression, and depress HIV susceptibility, and we propose studies to examine the molecular basis for this effect as well. We believe these studies will contribute significantly to our understanding of the molecular basis for the effects of opioids on the neuropathology associated with HIV infection.

最近的研究表明，阿片类药物的使用会改变对多种传染源的易感性， 包括人类免疫缺陷病毒（HIV）。据估计，三分之一的艾滋病毒感染者 这个国家有静脉阿片类药物滥用者。然而，人们对阿片类药物的影响知之甚少 滥用艾滋病毒感染中枢神经系统 (CNS) 或相关神经系统疾病，包括 失智。目前的证据表明，病毒向中枢神经系统的最初传播涉及贩运 在感染急性期感染血源性单核细胞。单核细胞的运输 中枢神经系统是一种正常的生理过程，但在炎症和/或与以下因素相关时会增强： 大脑感染。我们实验室以及其他实验室报告的证据表明，阿片类药物可能 促进导致受感染细胞迁移到大脑的贩运过程。我们对此的假设 应用是阿片类药物具有显着的能力，通过改变艾滋病毒脑炎的发展 关键趋化因子和趋化因子受体的表达。我们认为阿片类药物的管理 促进促炎单核细胞的发育，该单核细胞具有增强的能力 产生并响应促炎趋化因子，并凭借更大的贩运能力，加速 病毒感染细胞进入大脑的过程。在这个资助项目中，我们将研究阿片类药物的效果 施用对促炎单核细胞表型的发育。我们将确定分子 mu 和 kappa 阿片类药物对关键趋化因子受体 CCR2 表达影响的机制，以及 作为非常重要的促炎趋化因子MCP-1。我们的实验室表明急性μ阿片类药物 给药诱导趋化因子受体 CCR5 和 CXCR4 的表达。我们将扩展这些 使用 CCR2 克隆分子构建体来确定这些效应的生化基础的研究 和MCP-1启动子。相反，我们的结果表明 kappa 阿片类药物抑制 HIV-1 辅助受体表达， 并降低艾滋病毒易感性，我们还建议进行研究来检验这种效应的分子基础。 我们相信这些研究将极大地有助于我们理解影响的分子基础 阿片类药物对 HIV 感染相关神经病理学的影响。