Opiate induced SIV-Neuropathogenesis: Role of miRNA-29b in the Periphery-CNS Cro

阿片诱导的 SIV 神经发病机制：miRNA-29b 在外周 CNS Cro 中的作用

• 批准号: 8476570
• 负责人: Shilpa J. Buch
• 金额: $ 43.64万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8476570
• 关键词: AIDS neuropathy; Acceleration; Acute; Address; Alzheimer' s Disease; Anti-Retroviral Agents; Archives; Area; Autopsy; Basal Ganglia; Biological Assay; Biological Markers; Biology; Brain; CCR5 gene; Cells; Chemosensitization; Chronic; Chronology; Cognitive deficits; Computational algorithm; Controlled Study; Data; Development; Disease; Disease Outcome; Disease Progression; Drug abuse; Funding; Future; Gene Expression; Genes; Glean; Goals; Grant; HIV; HIV Infections; HIV-1; Healthcare; Heroin Abuse; Human; In Situ Hybridization; In Vitro; Individual; Infection; Link; Macaca; Macaca mulatta; Mediating; MicroRNAs; Modeling; Molecular; Morphine; Morphine Dependence; Neurodegenerative Disorders; Neurologic Deficit; Neuropathogenesis; Opiates; Parents; Parkinson Disease; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Regulation; Research; Role; SIV; Sampling; Severity of illness; Staging; Syndrome; Testing; Time; Tissues; Up-Regulation; Validation; Viral; Virus Diseases; base; brain tissue; clinically relevant; cohort; cost; end stage disease; expectation; global health; innovation; insight; mortality; neuroinflammation; neuron apoptosis; neuronal survival; neuropathology; neurotoxicity; neurotropic; opioid abuse; public health relevance; receptor; research study; therapeutic target

DESCRIPTION (provided by applicant): Opiate abuse and HIV-1 have been described as two linked global health crises, and despite the advent of anti-retroviral therapy, abuse of opiates has been shown to result in increased neurologic and cognitive deficits. Using the morphine-dependent rhesus macaques (RM) infected with CCR5-utilizing SIVR71/17E we recapitulated the human syndrome demonstrating augmentation of neuropathology & neuroinflammation and rapid disease progression compared with SIV-infected controls. Mortality in these rapid progressors was associated with robust viral replication in both the periphery & the brain. MicroRNA (miR)-mediated regulation of disease pathogenesis represents an evolving area of research that has ramifications for identification of potential therapeutic targets for various neurodegenerative disorders for which currently there exists no cure. Based on the similarities between the chronology of lentiviral infection in humans and macaques, the SIV/RM model offers a unique platform to perform controlled studies on the role of morphine in potentiating disease pathogenesis. The goal of the present application is to address how interactions between morphine & SIV in the acute phase of infection impact disease outcome in the chronic stage in the context of miR-mediated regulation of neurotoxicity. The innovative aspects of this proposal are based on our unique observation that in chronically (SIV)-infected RMs, morphine mediated potentiation of neuropathogenesis correlates with dysregulation of miRs, with specific upregulation of miR-29b (that is also upregulated in Alzheimer's & Parkinsons diseases) in both the peripheral blood mononuclear cells (PBMCs) as well as post mortem brain tissue. The hypotheses to be tested are that: a) morphine-mediated potentiation of SIV neuropathogenesis involves, in part, upregulation of miR-29b during the early (acute phase) of infection and, b) based on target identification using computer algorithms upregulation of miR-29b is critical for regulating genes controlling neuronal survival such as the platelet-derive growth factor (PDGF) and its receptor (PDGF-R) dyad. Specific Aim 1 will be aimed at tracking morphine-mediated dysregulation of miR profiles (with emphasis on miR-29b) in the periphery & CNS of SIV-infected macaques during acute (14d pi) infection. These will be compared miR data obtained from the historical archived tissues of chronically infected RMs [ongoing parent study]. Specific Aim 2 will test the hypothesis that morphine-induced alteration in miR-29b targets the expression of neurotropic factors such as platelet-derived growth factor (PDGF) and its receptor, culminating into increased neuronal apoptosis.

描述（由申请人提供）：阿片类药物滥用和HIV-1被描述为两种联系的全球健康危机，尽管抗逆转录病毒疗法出现了，但滥用鸦片的滥用会导致神经系统和认知缺陷增加。使用吗啡依赖性的猕猴（RM）感染了CCR5利用SIVR71/17E，我们概括了人类综合征，表明与SIV感染对照相比，神经病理学和神经炎症和快速疾病进展的增强。这些快速进步者的死亡率与外围和大脑的强大病毒复制有关。 microRNA（miR）介导的疾病发病机理的调节代表了一个不断发展的研究领域，该领域的影响是确定目前尚无治愈的各种神经退行性疾病的潜在治疗靶标的。基于人类和猕猴的慢病毒感染的年表之间的相似性，SIV/RM模型提供了一个独特的平台，以对吗啡在增强疾病发病机理中的作用进行受控研究。本应用的目的是解决在感染的急性阶段中吗啡和SIV之间的相互作用如何在miR介导的神经毒性调节的背景下影响慢性阶段的疾病结果。 The innovative aspects of this proposal are based on our unique observation that in chronically (SIV)-infected RMs, morphine mediated potentiation of neuropathogenesis correlates with dysregulation of miRs, with specific upregulation of miR-29b (that is also upregulated in Alzheimer's & Parkinsons diseases) in both the peripheral blood mononuclear cells (PBMCs) as well as post尸体脑组织。 The hypotheses to be tested are that: a) morphine-mediated potentiation of SIV neuropathogenesis involves, in part, upregulation of miR-29b during the early (acute phase) of infection and, b) based on target identification using computer algorithms upregulation of miR-29b is critical for regulating genes controlling neuronal survival such as the platelet-derive growth factor (PDGF) and its receptor （PDGF-R）二元。具体目标1将旨在跟踪吗啡介导的miR谱的失调（重点是miR-29b）在急性（14d PI）感染期间SIV感染猕猴的外围和CNS中。这些将被比较从慢性感染RMS的历史存档组织中获得的miR数据[正在进行的父母研究]。具体目标2将检验以下假设：吗啡诱导的miR-29b的改变靶向神经性因子的表达，例如血小板衍生的生长因子（PDGF）及其受体，最终导致神经元凋亡增加。