DYNORPHIN AND GLIAL CELL IMMUNOMODULATION

强啡肽和胶质细胞免疫调节

• 批准号: 2713127
• 负责人: PHILLIP Keith PETERSON
• 金额: $ 24.53万
• 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 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2713127
• 关键词: AIDS dementia complex; cytokine; dynorphins; endogenous opioid; glia; human immunodeficiency virus 1; immunomodulators; inhibitor /antagonist; nitric oxide; opioid receptor; tissue /cell culture

The immunomodulatory opioid peptides have been implicated in the neuroimmunopathogenesis of human immunodeficiency virus (HIV)-1 infection and acquired immunodeficiency syndrome (AIDS) dementia However, little is known about the impact of the endogenous opioid peptides (EOP) on the replication of HIV-1 within the brain and on the neurotoxic effect of HIV- 1-related proteins (e.g., gp12O and tat). Our principal hypothesis is that kappa opioid peptides play an immunomodulatory role in the central nervous system via their interaction with specific receptors on glial cells (i.e., microglia and astrocytes), and that this interaction enhances cytokine and nitric oxide (NO) production by these brain immune cells with consequences related to HIV-1 replication and injury in the brain. In vitro cultures of both fetal and adult human microglia and astrocytes will be used to characterize kappa opioid peptide receptors on human brain glial cells (Specific Aim l), to investigate the effect of kappa opioid peptides and of EOP receptor antagonists on HIV-1 replication in human brain cell cultures and purified microglial cell cultures (Specific Aim 2), and to assess the effect of kappa opioid peptides and of EOP receptor antagonists on gp120- and tat-induced neurotoxicity (Specific Aim 3). Glial cells, cytokines, and NO appear to play a central role in the neuropathogenesis of HIV-1 infection and HIV-1-related neurotoxicity. The effect of kappa opioid peptides and EOP receptor antagonists on cytokine production (e.g., tumor necrosis factor-alpha, interleukin [IL]-1, IL-6) by microglial cells and NO production by astrocytes will be explored. Furthermore, we have developed two models of HIV-1 SF162 infection of primary mixed glial/neuronal cell cultures and of enriched microglial cell cultures in order to explore the effect of kappa opioid peptides and of EOP receptor antagonists on HIV-1 replication. Finally, by using human fetal neuronal cell cultures, we will assess the effect of kappa opioid peptides and of EOP receptor antagonists on gpl20- and tat-induced neurotoxicity. These studies of brain immune cells, a target cell population not only for kappa opioid peptides but also for HIV-1 infection, will contribute to our goals of understanding the role of endogenous opioid peptides in the neuroimmunopathogenesis of AIDS in conditions associated with stress including opiate addiction and of devising therapeutic tools that interfere with the development of AIDS dementia.

免疫调节阿片肽与 人类免疫缺陷病毒（HIV）-1感染的神经免疫发病机制 和获得性免疫缺陷综合症（艾滋病）痴呆症 已知内源性阿片肽（EOP）对 HIV-1 在大脑内的复制以及 HIV-1 的神经毒性作用 1 相关蛋白（例如 gp12O 和 tat）。我们的主要假设是 kappa阿片肽在中枢神经中发挥免疫调节作用 系统通过与神经胶质细胞上的特定受体相互作用（即， 小胶质细胞和星形胶质细胞），并且这种相互作用增强了细胞因子和 这些脑免疫细胞产生一氧化氮 (NO) 并产生后果 与 HIV-1 复制和大脑损伤有关。体外培养 胎儿和成人的小胶质细胞和星形胶质细胞都将用于 表征人脑胶质细胞上的 kappa 阿片肽受体 （具体目标 l），研究 kappa 阿片肽和 EOP受体拮抗剂对人脑细胞中HIV-1复制的影响 培养物和纯化的小胶质细胞培养物（具体目标 2），以及 评估 kappa 阿片肽和 EOP 受体拮抗剂的作用 关于 gp120 和 tat 诱导的神经毒性（具体目标 3）。胶质细胞， 细胞因子和 NO 似乎在神经发病机制中发挥核心作用 HIV-1 感染和 HIV-1 相关的神经毒性。卡帕的效果 阿片肽和 EOP 受体拮抗剂对细胞因子产生的影响（例如， 小胶质细胞产生的肿瘤坏死因子-α、白细胞介素 [IL]-1、IL-6） 星形胶质细胞产生一氧化氮的情况也将被探索。此外，我们还有 开发了两种HIV-1 SF162原发性混合感染模型 神经胶质细胞/神经元细胞培养物和富集的小胶质细胞培养物 为了探索κ阿片肽和EOP受体的作用 HIV-1复制拮抗剂。最后，通过使用人类胎儿神经元 细胞培养物中，我们将评估 kappa 阿片肽和 EOP 受体拮抗剂对 gpl20 和 tat 诱导的神经毒性。这些 脑免疫细胞的研究，目标细胞群不仅是 kappa 阿片肽以及针对 HIV-1 感染的药物，将有助于实现我们的目标 了解内源性阿片肽在 压力相关条件下艾滋病的神经免疫发病机制 包括鸦片成瘾和设计治疗工具 干扰艾滋病痴呆症的发展。