Glial Progenitors as Targets of HIV/Opiate Interactions

神经胶质祖细胞作为艾滋病毒/阿片类药物相互作用的目标

基本信息

批准号：
8732215
负责人：
Pamela E Knapp
金额：
$ 37.99万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8732215
关键词：
3-Dimensional Acetylcysteine Adolescent Adult Affect Animals Astrocytes Autopsy Behavior Binding Brain Bromodeoxyuridine CCR5 gene Cell Count Cell Lineage Cell Maturation Cell Proliferation Cell Separation Cell Volumes Cell model Cell physiology Cells Characteristics Chronic Cognitive Complex Corpus striatum structure Data Development Disease Enhancers Epidemic Exploratory Behavior Exposure to Functional disorder Funding Glial Fibrillary Acidic Protein HIV HIV Infections HIV-1 Heroin Abuse Hippocampus (Brain)Human Image In Vitro Individual Infection Inflammation Inflammatory Injection of therapeutic agent Injury Longitudinal Studies Mediating Microglia Modeling Morphine Motor Mus NADPH Oxidase NG-Nitroarginine Methyl Ester NOS2A gene Neurocognitive Neuroepithelial Neuroglia Neurons Nitric Oxide Oligodendroglia Opiates Outcome Oxidation-Reduction Play Population Prodrugs Production Proteins Public Health Regimen Risk Role Schedule Second Messenger Systems Signal Pathway Signal Transduction Staging Stem cells System Testing Therapeutic Agents Time Tissues Transgenic Model Transgenic Organisms Undifferentiated Viral Work acetovanillone aminoguanidine cell behavior cellular imaging dentate gyrus ethyl pyruvate extracellular gliogenesis heme oxygenase-1 high risk human NOS2A protein in vivo inhibitor/antagonist injection drug use lateral ventricle macroglia macrophage migration nerve stem cell neurogenesis novel opioid abuse progenitor public health relevance repaired second messenger subventricular zone theories

项目摘要

DESCRIPTION (provided by applicant): HIV-infected individuals who abuse heroin are at greater risk for HAND. The synaptodendritic injury that underlies HAND is largely mediated by infected and/or activated microglia and astroglia as neurons are rarely, if ever, infected. CNS neurons and glia are derived from neuroepithelial precursors in the subventricular zone (SVZ). In development, undifferentiated, common "neural progenitor cells" (NPCs) give rise to cells that form neurons, astroglia, and oligodendroglia on a precise schedule of proliferation, migration, and differentiation regulated by complex intra- and extracellular signals. In the mature CNS, neurogenesis is largely limited to specific regions (dentate gyrus and SVZ of lateral ventricles), while gliogenesis also occurs in the parenchyma. During the 1st funding period, we showed that HIV-1 and HIV proteins diminished NPC ability to differentiate and populate the striatum, in mice exposed both perinatally and as adults, and in vitro. In general, HIV R5 (culture) and HIV-1 Tat (in vivo stereology; culture) reduced Sox2+ NPCs and slowed proliferation. HIV-1 Tat in vivo also seemed to redirect cell fate as mature cell populations were changed ( oligodendroglia, astroglia) while total cell numbers and volume were normal. Co-exposure to morphine exacerbated some outcomes. Thus, both HIV and Tat interfere with NPC development via mechanisms that opiates can amplify. Data demonstrate that R5 or chronic Tat exposure distort normal NPC microglia interactions, resulting in abnormal CNS populations. Imbalances ( inflammatory astroglia, myelinating OLs) likely contribute to HIV-related deficits in CNS function. We hypothesize that HIV by itself, and more potently with morphine, overactivate microglia, causing aberrant signaling to NPCs through NADPH oxidase (NOX2) and iNOS/nitric oxide. The inappropriate signaling misdirects NPC lineage/differentiation, ultimately altering CNS cell populations. This theory is explored in vivo (mouse/HIV-1 Tat model) and in human brain cultures (HIV infective model) in 2 related aims. Aim 1 tests if microglia play a central rol in the aberrant proliferation/lineage of NPCs after exposure to HIV-1 Tat ± opiates. Studies use a macrophage/ microglia deficient transgenic model (HIV-1 Tat x CSF1op/op mice), with chronic Tat induction at both adolescent (high risk for HIV and opiate exposure through exploratory behaviors) and adult stages. Hippocampus and striatum are studied; motor and cognitive behaviors correlated to population changes. NPCs are also examined in HIV+/HIV- autopsy tissue. Aim 2 tests the roles of microglial NOX2 and iNOS signaling as causal in dysregulated NPC dynamics, using 3-dimensional aggregate cultures from human brain and real-time tracking of individual human NPCs±HIV±opiates±specific inhibitors of iNOS, NOX2 and R5 binding. Amnis flow-single cell imaging used to identify infected cells.

描述（由适用提供）：滥用海洛因的艾滋病毒感染者面临更大的手感风险。构成手基的突触性损伤在很大程度上是由感染和/或活化的小胶质细胞和星形胶质细胞介导的，因为神经元很少被感染。中枢神经系统神经元和神经胶质是源自脑室内区域（SVZ）的神经上皮前体。在发育中，未分化的常见“神经祖细胞”（NPC）会产生形成神经元，星形胶质细胞和少突胶质细胞的细胞，这是由复杂的细胞内和外细胞外信号调节的精确进度。在成熟的中枢神经系统中，神经发生在很大程度上仅限于特定区域（齿状回和侧心室的SVZ），而神经胶质发生也发生在实质中。在第一个资金期间，我们表明HIV-1和HIV蛋白降低了NPC分化和填充纹状体的能力，在围产期和成年人以及体外暴露的小鼠中。通常，HIV R5（培养）和HIV-1 TAT（体内立体学；培养）减少了SOX2+ NPC，并减慢了增殖。随着成熟的细胞群的改变（少突endroglia，Astroglia），而总细胞数量和体积正常，体内的HIV-1 TAT似乎也重定向细胞命运。对吗啡的共曝光加剧了一些结果。艾滋病毒和TAT都通过运作的机制来干扰NPC的开发，可以放大。数据表明，R5或慢性TAT暴露会扭曲正常的NPC小胶质细胞相互作用，导致中枢神经系统种群异常。失衡（炎症性星形胶质细胞，骨髓OL）可能导致与HIV相关的中枢神经系统功能缺陷。我们假设艾滋病毒本身，并且更可能与吗啡过度活化的小胶质细胞，从而通过NADPH氧化酶（NOX2）和ionos/nirric氧化物引起NPC的异常信号。不当信号传导误导了NPC谱系/分化，最终改变了CNS细胞群体。在2个相关目的中，在体内（小鼠/HIV-1 TAT模型）和人脑培养物（HIV感染模型）中探讨了该理论。 AIM 1测试是否在暴露于HIV-1 TAT±操作后NPC的异常增殖/谱系中，小胶质细胞在异常的谱系中起中心作用。研究使用巨噬细胞/小胶质细胞不足的转基因模型（HIV-1 TAT X CSF1OP/ OP小鼠），在两种青春期（HIV的高风险和通过探索性行为来优化暴露）和成人阶段和成人阶段都具有慢性TAT诱导。海马和纹状体是研究的；运动和认知行为与种群变化有关。 NPC在HIV+/HIV-尸检组织中也进行了检查。 AIM 2使用来自人脑的3维骨料培养物以及单个人类NPCS±HIV±opiates的实时跟踪±iNOS，NOOS，NOX2和R5结合的特定抑制剂的小胶质细胞NOX2和INOS信号作为因果NPC动力学中因果关系的作用。 amnis流环细胞成像用于鉴定受感染的细胞。