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

描述(申请人提供)：阿片剂滥用和艾滋病毒-1被描述为两个相互关联的全球健康危机，尽管出现了抗逆转录病毒治疗，但阿片剂的滥用已被证明导致神经和认知缺陷的增加。使用感染CCR5的吗啡依赖恒河猴(RM)，利用SIVR71/17E，我们重现了人类的综合征，与SIV感染的对照组相比，显示了神经病理和神经炎症的增强和疾病的快速进展。这些快速进展者的死亡率与周围和大脑中强劲的病毒复制有关。MicroRNA(MiR)介导的疾病发病机制调控是一个不断发展的研究领域，对于确定目前尚无治愈方法的各种神经退行性疾病的潜在治疗靶点具有重要意义。基于人类和猕猴慢病毒感染年表的相似性，SIV/RM模型提供了一个独特的平台来进行吗啡在增强疾病发病机制中的作用的对照研究。本申请的目的是在miR介导的神经毒性调节的背景下，解决感染急性期吗啡和SIV之间的相互作用如何影响慢性期的疾病结局。这项建议的创新方面是基于我们独特的观察，在慢性(SIV)感染的RMS中，吗啡介导的神经发病增强与miRs的调节失调相关，在外周血单个核细胞(PBMCs)以及死后脑组织中miR-29b(这在阿尔茨海默氏症和帕金森病中也上调)的特异性上调。需要检验的假设是：a)吗啡介导的SIV神经发病机制的增强部分涉及感染早期(急性期)miR-29b的上调，以及b)基于计算机算法的靶标识别，miR-29b的上调对于调控控制神经元存活的基因如血小板衍生生长因子(PDGF)及其受体(PDGF-R)二联体至关重要。具体目标1将旨在追踪急性(14d Pi)感染SIV的猕猴外周和中枢神经系统中由吗啡介导的miR图谱的失调(重点是miR-29b)。这些将与从慢性感染的RMS的历史存档组织中获得的miR数据进行比较[正在进行的父母研究]。《特殊目的2》将测试一种假设，即吗啡诱导miR-29b的改变以血小板衍生生长因子(PDGF)及其受体等神经营养因子的表达为靶点，最终导致神经细胞凋亡增加。

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.