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：
7389104
负责人：
Pamela E Knapp
金额：
$ 33万
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 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7389104
关键词：
1-Phosphatidylinositol 3-Kinase AIDS neuropathy Acquired Immunodeficiency Syndrome Adult Affect Astrocytes Brain Bromodeoxyuridine CCL2 gene CD44 gene Cells Cessation of life Childhood Chronic Coculture Techniques Commit Complex Corpus striatum structure Data Disease Disruption Drug usage End Point Epidemic Equilibrium Exposure to GLAST Protein Genetic Glutamates HIV HIV Envelope Protein gp120 HIV Infections HIV encephalitis HIV-1 Heroin Abuse Human Human immunodeficiency virus test Immune response In Situ In Situ Nick-End Labeling In Vitro Individual Infection Inflammation Inflammatory Injection of therapeutic agent Interleukin-6 Mediating Medical Microglia Modeling Molecular Morphine Mus Needle Sharing Neonatal Neuroepithelial Neuroglia Neurons Numbers Oligodendroglia Opiates Opioid Receptor PTEN gene Pathogenesis Pathway interactions Patients Peripheral Population Predisposition Prevalence Process Production Protein Overexpression Proteins Public Health Research Risk Role SCID Mice Signal Transduction Small Interfering RNA Source Specificity Staging System TNF gene Testing Therapeutic Time Tissues Toxic effect Toxin Transgenic Mice Treatment Protocols Undifferentiated Up-Regulation Viral Viral Proteins Virus Work base caspase-3 cell type chemokine combinatorial cytokine day drug of abuse endonuclease G human tissue illness length in vivo monocyte mouse model mu opioid receptors neonate neuropathology neurotoxic neurotoxicity opioid abuse progenitor receptor receptor expression research study response social synergism uptake virotoxins

项目摘要

DESCRIPTION (provided by applicant): Heroin abuse increases the risk of HIV infection and may exacerbate HIV encephalitis (HIVE). Since a large percentage of newly infected HIV patients abuse opiates, this enhancement of disease process has serious medical and social consequences. Little is known about cellular mechanisms by which opiates accelerate and enhance the CNS neuropathology associated with HIV infection, and synergism may be multifactorial. Recent evidence from our labs and others suggests that precursors of CNS cells can be targets of HIV-mediated toxicity. Our central hypothesis is that HIV proteins and/or HIV can target glial precursors in the CNS, and that opiates act synergistically to enhance the toxic effects of HIV. Even modest toxicity toward this population would, over time, alter the balance of glial cells and glial-neuronal relationships in the mature CNS. The net consequences would depend upon the differential sensitivity of glial precursors at each stage of maturation, and likely would be influences by the onset and duration of disease, and timing of therapeutic regimens. Based on initial data showing that glial precursors and their progeny have different responses to Tat and morphine exposure, we propose aims that test if HIV viral proteins or HIV in combination with opiates alter production and/or survival of progenitors in vivo, thereby altering CNS mature glial populations (Aims 1 & 2). We also use in vitro approaches in isolated cells and more complex systems to assess intracellular pathways activated by viral toxins and opiates in glial progenitors (Aim 3). Aims 1 and 2 utilize three in vivo mouse models. The first is an inducible transgenic mouse expressing HIV-1 Tat in astroglia. The second is a gp120 i.c.v. injection model. The third is a SCID mouse injected with HIV-infected human monocytes. These aims assess glial progenitors in mature and neonatal mice, to understand the effects of HIV exposure on progenitors and glial populations in adult vs. pediatric situations. Human HIV tissue is also studied. Aim 3 uses pharmacologic and molecular strategies to explore disruptions in intracellular signaling in murine and human cells in vitro. Studies assess lethal and sub-lethal effects, and include pharmacological and genetic approaches to show that opiate-HIV synergism is mediated through mu-opioid receptors. In summary, there are compelling reasons to explore HIV-opiate synergy. Our comprehensive approach will provide accurate data about the susceptibility of glial precursors to HIV and opiate exposure in vivo, and potential long-term consequences to CNS pathology.HIV infection and injection drug use are interlinked epidemics with devastating consequences for public health. This project examines interactive effects between HIV and opiate drugs of abuse on glial progenitors and mature glial populations in the brain to define synergistic mechanisms that promote CNS neuropathology

描述（由申请人提供）：海洛因滥用会增加HIV感染的风险，并可能加剧HIV脑炎（HIVE）。由于很大一部分新感染的艾滋病毒患者滥用了鸦片，因此这种疾病过程的增强具有严重的医疗和社会后果。关于鸦片加速并增强与HIV感染相关的CNS神经病理的细胞机制知之甚少，并且协同作用可能是多因素。我们实验室和其他实验室的最新证据表明，中枢神经系统细胞的前体可能是HIV介导的毒性的靶标。我们的中心假设是，HIV蛋白和/或HIV可以靶向中枢神经系统中的神经胶质前体，并且阿片类药物具有协同作用，以增强HIV的毒性作用。随着时间的流逝，即使对该人群的适度毒性也会改变成熟中枢神经系统中神经胶质细胞和神经神经元关系的平衡。净后果将取决于在成熟阶段的神经胶质前体的差异敏感性，并且可能会受到疾病的发作和持续时间以及治疗方案的时间的影响。基于最初的数据表明，神经胶质前体及其后代对TAT和吗啡的暴露有不同的反应，我们提出的目的是测试HIV病毒蛋白或HIV与阿片类药片结合使用，改变了体内祖细胞的产生和/或存活，从而改变了CNS成熟的Glial Glial群体（目标1＆2）。我们还在孤立的细胞和更复杂的系统中使用体外方法来评估病毒毒素和神经胶质祖细胞中鸦片激活的细胞内途径（AIM 3）。 AIMS 1和2利用三个体内鼠标模型。第一个是一种在星形胶质细胞中表达HIV-1 TAT的诱导型转基因小鼠。第二个是GP120 I.C.V.注射模型。第三个是注射HIV感染的人单核细胞的SCID小鼠。这些目的评估成熟和新生小鼠中的神经胶质祖细胞，以了解艾滋病毒暴露对成人与儿科情况下祖细胞和神经胶质种群的影响。还研究了人类HIV组织。 AIM 3使用药理学和分子策略来探索体外鼠和人类细胞中细胞内信号传导的破坏。研究评估了致命和亚致死作用，并包括药理学和遗传学方法，以表明阿片类HIV的协同作用是通过MU-Apioid受体介导的。总而言之，有令人信服的理由探索艾滋病毒 - 适应性协同作用。我们的全面方法将提供有关神经胶质前体对艾滋病毒和体内暴露的敏感性的准确数据，以及对CNS病理学的潜在长期后果。HIV感染和注射药物使用是与公共卫生造成毁灭性后果的相互联系的流行病。该项目研究了艾滋病毒和鸦片药物之间对神经胶质祖细胞和大脑成熟的神经胶质种群之间的互动效果，以定义促进CNS神经病理学的协同机制