DYNORPHIN AND GLIAL CELL IMMUNOMODULATION

强啡肽和胶质细胞免疫调节

• 批准号: 6634221
• 负责人: PHILLIP Keith PETERSON
• 金额: $ 26.59万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634221
• 关键词: AIDS /HIV neuropathy; AIDS dementia complex; antiviral agents; chemokine; dynorphins; embryo /fetus tissue /cell culture; endogenous opioid; glia; human immunodeficiency virus 1; human tissue; immunomodulators; inhibitor /antagonist; neuroprotectants; neurotoxicology; nuclear factor kappa beta; opioid receptor; tissue /cell culture; virus replication

Endogenous opioid peptides have been postulated to modulate the neuropathogenesis of human immunodeficiency virus (HIV)-1, the etiologic agent of acquired immunodeficiency syndrome (AIDS) dementia. The principal hypothesis of the work proposed in this grant renewal application is that kappa opioids have a neuroprotective role in HIV-l-induced brain disease by suppressing HIV-1 expression and by reducing viral-induced neuronal injury. In the past several years, we have found that kappa opioid receptor (KOR) ligands inhibit HIV-1 expression in acutely infected human microglial cell cultures. In preliminary studies, KOR ligands also appear to suppress viral expression in cultures of human monocytes, the precursor cells of microglia. Although the mechanism of this antiviral effect has not yet been elucidated, kappa opioids are proposed to trigger a cascade of cellular events resulting in reduced viral expression by one or more of the following mechanisms: 1) inhibition of viral entry into target cells, 2) reduced activation of nuclear factor-kappaB, a cellular transcription factor required for the activation of the HIV-1 replication, 3) suppression of HIV-1 promoter activity, or 4) potentiation of the production of antiviral beta-chemokines by opioid-treated cells. Also, the anti-viral effects of U5O,488 will be tested using primary HIV-1 isolates (Specific Aim l). In addition to their antiviral activity, KOR ligands will be evaluated for their neuroprotective activity against HIV-1-induced toxicity using the HIV-l SF162 strain and primary isolates. The protective mechanism of KOR ligands is postulated to involve either l) an indirect mechanism by inhibiting microglial cell- and monocyte- induced production of neurotoxins (i.e., quinolinate, Tat, or cytokines [interleukin-1beta and tumor necrosis factor-alpha] or 2) a direct mechanism protecting neurons against toxicity induced by these toxins (Specific Aim 2). The findings from these studies will potentially provide insights into mechanisms associated with antiviral and neuroprotective effects of kappa opioids and hopefully will lead to development of new therapeutic approaches for AIDS dementia.

内源性阿片肽被认为调节人类免疫缺陷病毒（HIV）-1的神经发病机制，HIV-1是获得性免疫缺陷综合征（AIDS）痴呆的病原体。在该授权更新申请中提出的工作的主要假设是κ阿片类药物通过抑制HIV-1表达和通过减少病毒诱导的神经元损伤在HIV-1诱导的脑疾病中具有神经保护作用。在过去的几年中，我们发现κ阿片受体（KOR）配体抑制急性感染的人类小胶质细胞培养物中的HIV-1表达。在初步研究中，KOR配体似乎也抑制了人单核细胞（小胶质细胞的前体细胞）培养物中的病毒表达。虽然这种抗病毒作用的机制尚未阐明，但提出κ阿片类药物通过以下一种或多种机制触发细胞事件级联，导致病毒表达降低：1）抑制病毒进入靶细胞，2）减少核因子-κ B的激活，所述核因子-κ B是激活HIV-1复制所需的细胞转录因子，3）抑制HIV-1启动子活性，或4）通过阿片样物质处理的细胞增强抗病毒β-趋化因子的产生。此外，将使用原代HIV-1分离株（特异性Aim 1）检测U 50，488的抗病毒作用。除了它们的抗病毒活性之外，还将使用HIV-1 SF 162菌株和原代分离株评价KOR配体针对HIV-1诱导的毒性的神经保护活性。1）通过抑制小胶质细胞和单核细胞诱导的神经毒素产生的间接机制（即，喹啉酸、达特或细胞因子[白细胞介素-1 β和肿瘤坏死因子-α]或2）保护神经元免受这些毒素诱导的毒性的直接机制（特异性目的2）。这些研究的结果将可能为kappa阿片类药物的抗病毒和神经保护作用相关机制提供见解，并有望为艾滋病痴呆症的新治疗方法的开发提供帮助。