DYNORPHIN AND GLIAL CELL IMMUNOMODULATION

免疫调节阿片肽被认为与 人类免疫缺陷病毒1型感染的神经免疫发病机制 和获得性免疫缺陷综合征(艾滋病)痴呆症，然而，几乎没有 已知内源性阿片肽(EOP)对 HIV-1在大脑中的复制及其对神经毒性的影响-- 1相关蛋白(如gp120和Tat)。我们的主要假设是 Kappa阿片肽在中枢神经系统中的免疫调节作用 系统通过它们与神经胶质细胞上的特定受体的相互作用(即， 小胶质细胞和星形胶质细胞)，这种相互作用增强了细胞因子和 这些大脑免疫细胞产生一氧化氮(NO)及其后果 与HIV-1在大脑中的复制和损伤有关。红豆杉的体外培养 胎儿和成人的小胶质细胞和星形胶质细胞将用于 人脑胶质细胞上kappa阿片肽受体的特性 (特定目的L)，探讨kappa阿片肽和Kappa阿片肽的作用 EOP受体拮抗剂对HIV-1在人脑细胞中复制的影响 培养和纯化小胶质细胞培养物(特定目标2)，并 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(特定目标3)。神经胶质细胞， 细胞因子和一氧化氮似乎在神经发病机制中起中心作用。 HIV-1感染和与HIV-1相关的神经毒性。卡帕的作用 阿片肽和EOP受体拮抗剂对细胞因子产生的影响(例如， 小胶质细胞分泌肿瘤坏死因子-α、白介素1、白介素6 而且不会探索星形胶质细胞的生产。此外，我们还拥有 建立两种HIV-1 SF162原代混合感染模型 神经胶质细胞/神经细胞培养和浓缩小胶质细胞培养 探讨kappa阿片肽和EOP受体的作用 HIV-1复制的拮抗剂。最后，通过使用人类胚胎神经元 细胞培养，我们将评估kappa阿片肽和 Eop受体拮抗剂对gpl20和tat诱导的神经毒性的影响。这些 脑免疫细胞的研究，靶细胞群不仅为kappa 阿片肽还可用于HIV-1感染，将有助于我们的目标 了解内源性阿片肽在血管紧张素转换酶中的作用 应激相关条件下艾滋病的神经免疫病理机制 包括鸦片成瘾和设计治疗工具 干预艾滋病痴呆症的发展。

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.