Neuronal transport of gp120

gp120 的神经元运输

• 批准号: 6798578
• 负责人: Italo Mocchetti
• 金额: $ 17.92万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6798578
• 关键词: AIDS dementia complex; HIV envelope protein gp120; apoptosis; brain mapping; brain septal area; central neural pathway /tract; chemokine receptor; corpus striatum; hippocampus; histopathology; laboratory rat; neuronal transport; neuropathology; neurotoxins; sciatic nerve; spinal ganglion; substantia nigra; tissue /cell culture; virus infection mechanism

DESCRIPTION (provided by applicant): Patients with Acquired Immune Deficiency Syndrome-related Dementia (AIDSD) exhibit a broad spectrum of motor impairments and cognitive deficits, which follow or parallel cellular loss, atrophy and morphological changes in their brains. The viral envelope glycoprotein gp120 has been suggested to be a causal agent of neuronal loss. However, little is known about the molecular and cellular mechanisms of this effect. The aim of the present study is to test the novel and challenging but timely hypothesis that gp120, released from microglia or astrocytes, causes apoptotic cell death by being internalized by neurons and retrogradely transported to neuronal cell bodies. We plan to test this hypothesis by using two strains of gp120, IIIB and BaL, which bind to CXCR4 and CCR5 chemokine receptors, respectively. Gp120 will be acutely injected into two well-established neuronal pathways of the rat brain, the nigrostriatal and septohippocampal pathways. In particular, we will inject gp120 into the caudate nucleus or fimbria and examine gp120 immunoreactivity in the substantia nigra and septal nuclei, respectively. These studies will be followed by analyses of cell types transporting gp120 by using antibodies against specific neuronal and non-neuronal markers. In addition, we will examine whether neurons positive for gp120 show signs of apoptosis by histologically measuring active caspase-3,-8 and -9. Moreover, we will investigate the hypothesis that gp120 may enter the central nervous system by axonal retrograde transport from peripheral nerves. The rat sciatic nerve will be exposed to gp120 and gp120 immunoreactivity will be determined in dorsal root ganglia and motor neurons of lumbar spinal cord. The retrograde transport hypothesis will be further tested by ligating the sciatic nerve to block axonal transport and examining gp120 accumulation. Overall, the results of the present study will provide a major break-through on the mechanisms whereby gp120 causes neuronal cell death and the related morphological alterations that may account for the motor and cognitive deficits found in AIDSD.

描述（由申请人提供）：患有获得性免疫缺陷综合症相关痴呆（AIDSD）的患者表现出广泛的运动障碍和认知缺陷，这些缺陷伴随或平行于大脑中的细胞损失、萎缩和形态变化。病毒包膜糖蛋白 gp120 被认为是神经元损失的致病因素。然而，人们对这种效应的分子和细胞机制知之甚少。本研究的目的是测试新颖且具有挑战性但及时的假设，即小胶质细胞或星形胶质细胞释放的 gp120 通过被神经元内化并逆行转运至神经元细胞体而导致细胞凋亡。我们计划使用 gp120 IIIB 和 BaL 两种菌株来检验这一假设，它们分别与 CXCR4 和 CCR5 趋化因子受体结合。 Gp120 将被快速注射到大鼠大脑的两条完善的神经元通路中，即黑质纹状体通路和隔海马通路。特别是，我们将 gp120 注射到尾状核或菌毛中，并分别检查黑质和隔膜核中的 gp120 免疫反应性。这些研究之后将使用针对特定神经元和非神经元标记的抗体来分析转运 gp120 的细胞类型。此外，我们将通过组织学测量活性 caspase-3、-8 和 -9 来检查 gp120 阳性神经元是否显示凋亡迹象。此外，我们将研究gp120可能通过轴突逆行转运从周围神经进入中枢神经系统的假设。将大鼠坐骨神经暴露于gp120，并在背根神经节和腰脊髓运动神经元中测定gp120免疫反应性。通过结扎坐骨神经以阻断轴突运输并检查 gp120 积累，将进一步检验逆行运输假说。总体而言，本研究的结果将为 gp120 导致神经元细胞死亡和相关形态改变的机制提供重大突破，这些改变可能解释 AIDS 中发现的运动和认知缺陷。