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，阿片类药物给药改变了对各种感染因子的易感性， 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， 这个国家是静脉注射阿片类药物滥用者。然而，人们对阿片类药物的影响知之甚少 中枢神经系统（CNS）或相关神经系统疾病（包括 痴呆目前的证据表明，病毒最初传播到中枢神经系统涉及运输病毒。 感染的血液来源的单核细胞在感染的急性期。单核细胞的运输到 CNS是正常的生理过程，但在炎症期间和/或与炎症相关时增强。 大脑的感染。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运输过程。我们的假设是 阿片类药物的应用是，阿片类药物具有显著的能力，通过改变HIV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使用 促进促炎性单核细胞的发育，这些单核细胞具有升高的能力， 产生并响应促炎趋化因子，并凭借更大的运输能力，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作用， 在一些实施方案中，本发明涉及促炎性单核细胞表型的发展。我们将确定 mu和kappa阿片类药物对关键趋化因子受体CCR 2表达的作用机制，以及 作为非常重要的促炎趋化因子MCP-1。我们的实验室已经证明急性μ阿片类药物 施用诱导趋化因子受体CCR 5和CXCR 4的表达。我们将把这些 使用CCR 2的克隆分子构建体来确定这些效应的生物化学基础的研究 和MCP-1启动子。相反，我们的研究结果表明，κ阿片类药物抑制HIV-1辅助受体的表达， 并降低艾滋病毒的易感性，我们建议研究，以检查这种影响的分子基础。 我们相信这些研究将大大有助于我们理解这些影响的分子基础 阿片类药物对与HIV感染相关的神经病理学的影响。