DYNORPHIN AND GLIAL CELL IMMUNOMODULATION

强啡肽和胶质细胞免疫调节

• 批准号: 2794136
• 负责人: PHILLIP Keith PETERSON
• 金额: $ 24.61万
• 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/2794136
• 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可以调节人类免疫缺陷病毒 (HIV)-1 的神经发病机制，人类免疫缺陷病毒 (HIV)-1 是获得性免疫缺陷综合征 (AIDS) 痴呆的病因。本次拨款更新申请中提出的工作的主要假设是，卡帕阿片类药物通过抑制 HIV-1 表达和减少病毒诱导的神经元损伤，在 HIV-1 诱导的脑部疾病中发挥神经保护作用。在过去的几年中，我们发现κ阿片受体（KOR）配体在急性感染的人小胶质细胞培养物中抑制HIV-1的表达。在初步研究中，KOR 配体似乎还能抑制人类单核细胞（小胶质细胞的前体细胞）培养物中的病毒表达。尽管这种抗病毒作用的机制尚未阐明，但卡帕阿片类药物被认为可以通过以下一种或多种机制触发一系列细胞事件，从而导致病毒表达减少：1）抑制病毒进入靶细胞，2）核因子-kappaB（一种激活 HIV-1 复制所需的细胞转录因子）的激活减少，3) 抑制 HIV-1 启动子活性，或 4) 增强抗病毒 β-趋化因子的产生由阿片类药物处理的细胞。此外，U5O,488 的抗病毒作用将使用主要 HIV-1 分离株进行测试（具体目标 l）。除了其抗病毒活性外，还将使用 HIV-1 SF162 毒株和初级分离株评估 KOR 配体针对 HIV-1 诱导毒性的神经保护活性。 KOR 配体的保护机制被假定涉及 l) 通过抑制小胶质细胞和单核细胞诱导的神经毒素（即喹啉、Tat 或细胞因子 [白介素-1β 和肿瘤坏死因子-α] 或 2）产生的间接机制。 ）保护神经元免受这些毒素诱导的毒性的直接机制（具体目标 2）。这些研究的结果将有可能深入了解与卡帕阿片类药物的抗病毒和神经保护作用相关的机制，并有望导致艾滋病痴呆症新治疗方法的开发。