Astrocyte Activation, Fas Ligand and HIV-1 Dementia

星形胶质细胞激活、Fas 配体和 HIV-1 痴呆

• 批准号: 6736959
• 负责人: Anuja Ghorpade
• 金额: $ 20.95万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6736959
• 关键词: AIDS dementia complex; CD95 molecule; apoptosis; astrocytes; cell population study; electrophysiology; enzyme linked immunosorbent assay; gene expression; human immunodeficiency virus 1; human subject; immunocytochemistry; immunoregulation; interleukin 1; laboratory rat; molecular pathology; morphometry; neurogenetics; neuroimmunomodulation; neuropharmacology; neurophysiology; neuroregulation; neurotoxicology; neurotoxins; polymerase chain reaction; protein structure function

DESCRIPTION (provided by the applicant): Astrocytes participate in maintenance of brain homeostasis and disease pathogenesis. Reactive astrogliosis is associated with neural injury in a wide range of neurodegenerative diseases, including HIV-1 -associated dementia (HAD). We hypothesize that activation of astrocytes may transform these normally supportive cells into neurotoxic immune effectors. Interleukin-I (IL-1) beta is elevated in HAD and is known to activate astrocytes, thus, we have chosen it as a prototypical immune activator. RT-PCR, ELISA and Immunocytochemistry analyses of IL-1 beta-activated astrocytes showed an upregulation of Fas ligand (FasL), a death protein. Elevated levels of FasL were observed in cerebrospinal fluid of HAD patients. Preliminary data showed that culture supernatants from IL-1 beta-activated astrocytes induced injury in rat and human neurons in cell-free and co-culture systems. Activated astrocytes led to caspase activation in human neurons. These findings lead us to believe that expression of FasL by activated astrocytes represents a novel pathway for neuronal injury in HAD. In order to explore this hypothesis, a series of cellular, molecular, pharmacological and electrophysiological techniques will be utilized to address the following questions: 1) What role does FasL play in astrocyte-mediated neuronal injury? 2) What is the mechanism for FasL-induced neurotoxicity? And 3) How is FasL expression regulated in activated astrocytes? We believe that answers to these questions will be important in understanding the mechanism of HAD and other neurodegenerative diseases and may provide novel approaches for therapeutic intervention.

描述（由申请人提供）：星形胶质细胞参与维持 脑稳态和疾病发病机制。反应性星形胶质细胞增多症是 与多种神经退行性疾病中的神经损伤有关， 包括 HIV-1 相关痴呆 (HAD)。我们假设激活 星形胶质细胞可能会将这些通常支持的细胞转化为神经毒性免疫细胞 效应器。白细胞介素-I (IL-1) beta 在 HAD 中升高，并且已知可激活 星形胶质细胞，因此，我们选择它作为原型免疫激活剂。逆转录聚合酶链反应， IL-1 β 激活星形胶质细胞的 ELISA 和免疫细胞化学分析显示 Fas 配体 (FasL)（一种死亡蛋白）的上调。 FasL 水平升高 在 HAD 患者的脑脊液中观察到。初步数据显示 IL-1β激活的星形胶质细胞的培养上清液诱导大鼠损伤 以及无细胞和共培养系统中的人类神经元。激活的星形胶质细胞 导致人类神经元中的半胱天冬酶激活。这些发现使我们相信 激活的星形胶质细胞表达 FasL 代表了一条新的途径 HAD 中的神经元损伤。为了探索这个假设，一系列的 细胞、分子、药理学和电生理学技术将 用于解决以下问题：1）FasL 在 星形胶质细胞介导的神经元损伤？ 2）FasL诱导的机制是什么 神经毒性？ 3）激活的星形胶质细胞中FasL的表达是如何调节的？ 我们相信这些问题的答案对于理解非常重要 HAD 和其他神经退行性疾病的机制，并可能提供新的 治疗干预的方法。