Astrocyte Activation, Dysfunction & Apoptosis in HAD

星形胶质细胞激活、功能障碍

• 批准号: 7016242
• 负责人: Dennis Larry Kolson
• 金额: $ 39.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7016242
• 关键词: AIDS dementia complex; CD95 molecule; apoptosis; astrocytes; disease /disorder model; embryo /fetus; glutamates; human subject; laboratory rat; neurons; neuroprotectants; neurotransmitter transport; tissue /cell culture; tumor necrosis factor alpha

The cardinal pathological features of HIV-associated dementia (HAD) include astrogliosis/activation, macrophage/microglia (M/M) activation, synaptic damage, and apoptosis of neurons and astrocytes. The mechanisms of M/M activation in HAD remain uncertain, but factors released by HIV-activated M/M (glutamate, Fas-L, TNF-alpha, viral proteins, others) are likely responsible for astrocytic & neuronal injury through multiple mechanisms. Moreover, astrocyte activation and injury are critical in amplifying neuronal damage, most likely through impairment of astrocyte high-affinity glutamate scavenging and related neuroprotective functions. The mechanisms by which HIV/MM injure astrocvtes have received relatively little attention despite the evidence that this is critical in HAD pathogenesis. Our hypothesis is that HIV-activated M/M induce both astrocyte and neuronal injury and apoptosis as well as astrocyte activation and associated dysfunction; and that this exacerbates neuronal injury through loss of neuroprotective functions such as glutamate scavenging. We have developed in vitro models for neuronal and astrocytic apoptosis and dysfunction and have shown that mitochondrial-mediated (intrinsic) apoptosis triggered by HIV-M/M excitotoxins defines a major pathway by which HIV-M/M injure neurons. We also established a unique human astrocyte cell model with inducible trans-gene expression, and have modulated mitochondrial-mediated astrocyte apoptosis through Bcl-2 expression. Furthermore, we found that Fas-L, which is unregulated in HAD brain, suppresses glutamate transport in astrocytes. and that TNF-alpha suppresses glutamate transport in astrocytes and enhances transport in M/M. Finally, we have carried out in vivo studies using a novel single cell mRNA amplification/gene profiling approach to begin to define gene expression patterns of individual brain cells in HAD. Our goal is to utilize our in vitro models to define the pathways of astrocyte activation and associated dysfunction & apoptosis elicited by HIV/MM, and exploit our in vivo gene expression analysis approach to define the pathways activated in vivo in HAD. We will: 1) Identify the mechanisms and pathways of astrocyte activation and apoptosis induced by HIV-M/M and the role of Fas death receptors; 2) Determine the mechanisms of death receptor (Fas, TNF) modulation of high-affinity glutamate transport in astrocytes and M/M and the effects on neuronal survival; and 3) Define the in vivo pathways of astrocyte apoptosis and the patterns of activation regulating high-affinity glutamate transporter expression in HAD using our single-cell mRNA analysis to validate and extend in vitro findings. Understanding the mechanisms of astrocyte injury in HAD may identify additional targets for comprehensive neuroprotection in HAD.

hiv相关性痴呆（HAD）的主要病理特征包括星形胶质细胞增生/活化、巨噬细胞/小胶质细胞（M/M）活化、突触损伤、神经元和星形胶质细胞凋亡。HAD中M/M激活的机制尚不清楚，但hiv激活M/M释放的因子（谷氨酸、Fas-L、tnf - α、病毒蛋白等）可能通过多种机制导致星形细胞和神经元损伤。此外，星形胶质细胞的激活和损伤很可能是放大神经元损伤的关键