HIV-OPN/SPP1Triad II: Molecular Pathways Regulating Neuronal-Glial Inflammation in the Brain

HIV-OPN/SPP1Triad II：调节大脑神经元胶质炎症的分子途径

基本信息

批准号：
10707336
负责人：
AMANDA MARIA BROWN
金额：
$ 79.36万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707336
关键词：
Adult Affective Aging Autopsy Basal Ganglia Behavior Biochemical Brain Buffers Cells Cerebellum Cerebral Ventricles Chemotactic Factors Chimera organism Chronic Cognition Cognitive Color Corpus striatum structure Detection Development Experimental Models Flow Cytometry Genetic Transcription Goals HIV HIV Infections Homeostasis Human ITGB3 gene Immune In Vitro Incidence Infection Inflammation Inflammatory Injury Integrins Investigation Ligands Liver Lung Macrophage Magnetic Resonance Imaging Mammals Measures Microglia Modification Molecular Mus Myeloid Cells Nerve Degeneration Neurologic Neurons Organ Pathway interactions Pattern Peripheral Persons Play Prevalence Primary Cell Cultures Proteins RNA RNA Splicing Receptor Signaling Recovery Reporting Residencies Resolution Role SIV Sampling Signal Transduction Specificity Spleen Structure of choroid plexus System Systemic infection Testing Therapeutic Time Tissues Tyrosine 3-Monooxygenase Variant Virus Replication antiretroviral therapy brain tissue chemokine chronic infection combinatorial cytokine humanized mouse in vivo insight knock-down microPET monocyte mouse model neuroAIDS neuroimaging neuroinflammation neuroprotection nigrostriatal dopaminergic pathway novel osteopontin receptor receptor expression response sensor sex tool trafficking

项目摘要

PROJECT SUMMARY The prevalence and incidence of neurological complications in people with HIV (PWH) remains steady for those aging on antiretroviral therapy (ART). Eliminating the tight association between chronic inflammation and HIV reservoirs in the periphery and CNS remain major therapeutic challenges. Elevated osteopontin/secreted phosphoprotein-1 (OPN/SPP1) in PWH having moderate to severe neurological complications was first reported in 2008. Since this time, the importance of high OPN/SPP1 RNA expression in human brain and more widely in neurodegenerative microglia has emerged. However, much remains to uncover about OPN/SPP1's fundamental basic molecular mechanism (s) of action in the brain in HIV infection. In this regard, our investigations over the past several years using in vitro and in vivo experimental models have begun to close the gap. A fundamental concept has emerged from our collective findings: OPN/SPP1 function is required in the CNS for brain recovery and return to homeostasis after infection. For the first time, able to knockdown OPN expression in vivo, we obtained a clearer view that its functional specificity is context- dependent. OPN/SPP1 signaling supports viral replication in vivo within tissue compartments via an as yet uncharacterized mechanism that varies with sex. In addition, OPN/SPP1 expression is strongly correlated with the retention of immune cells in the peripheral organs. OPN/SPP1 supports increased trafficking of SIV monocytes to the brain, but whether the same is true for human cells is not known. We discovered using micro- PET neuroimaging, that when homeostasis is disrupted by HIV infection, OPN/SPP1 is a potent sensor and regulator of neuroinflammation in the brain. An additional novel insight gained was the detection not only of inflamed microglia, but of a unique subset of “activated” translocator protein (TSPO) and tyrosine hydroxylase (TH) reactive neurons in the striatum. We hypothesize that the conservation of OPN as a sensor/regulator of CNS homeostasis in adult mammals suggests that it plays a key central mechanistic role in neuroprotective pathways that modulate neuroinflammation. Moreover, the molecular mechanisms are tissue context-dependent and utilize ligand-receptor dynamics initiated by microglia and propagated by specific neurons in the striatum. Teasing out of the mechanistic details requires a combinatorial approach using basic biochemical and molecular tools, in vitro primary cell culture and the latest in vivo chimeric mouse models. Importantly, we have successfully demonstrated that the mouse-human chimera represented in the NSG-hCD34 system recapitulates key aspects of neuroinflammation similar to that seen in people with neuroHIV. Testing of the underlying hypotheses of the integrated aims of this proposal will determine which splice variants of OPN/SPP1 are active in the CNS, identify new mechanistic insights into why disruption of OPN/SPP1 increases neuroinflammatory signaling in microglia and specific neuronal subtypes, how these responses are regulated and whether cognition or affective behaviors are altered.

项目摘要艾滋病毒（PWH）患者神经系统并发症的患病率和发病率保持稳定对于那些接受抗逆转录病毒疗法（ART）老龄化的人。消除慢性之间的紧密关联外围和中枢神经系统中的炎症和艾滋病毒水库仍然是主要的治疗挑战。高架骨桥蛋白/分泌的磷蛋白1（OPN/SPP1）中等至重度神经系统并发症于2008年首次报道。从那时起，高OPN/SPP1 RNA表达在人脑已经出现了，在神经退行性小胶质细胞中更广泛。但是，还有很多要发现了HIV感染中大脑中作用的OPN/SPP1的基本基本分子机制。在这方面，我们在过去几年中使用体外和体内实验模型的调查具有开始缩小差距。我们的集体发现出现了一个基本概念：OPN/SPP1功能中枢神经系统需要进行大脑恢复，并在感染后恢复体内平衡。第一次能够为了敲除体内的OPN表达，我们获得了更清晰的观点，即其功能特异性是上下文 - 依赖。 OPN/spp1信号传导通过AS在组织室内的体内支持病毒复制随着性别变化的未表征机制。此外，OPN/SPP1表达与免疫细胞在外周器官中的保留。 OPN/SPP1支持增加SIV的贩运对大脑的单核细胞，但人类细胞是否相同。我们发现了使用微型 PET神经影像学，当艾滋病感染破坏稳态时，opn/spp1是一个潜在的传感器，大脑中神经炎症的调节剂。获得的另一个新颖的见解不仅是检测发炎的小胶质细胞，但独特的“活化”易位蛋白（TSPO）和酪氨酸羟化酶的子集具有独特的子集（Th）纹状体中的反应性神经元。我们假设将OPN保存为传感器/调节器成人哺乳动物中的CNS稳态表明它在调节神经炎症的神经保护途径。此外，分子机制是组织上下文依赖性并利用小胶质细胞引发并通过纹状体中的特定神经元。从机械细节中取笑需要一种组合方法使用基本的生化和分子工具，体外原代细胞培养和最新的体内嵌合小鼠型号。重要的是，我们成功证明了小鼠 - 人类嵌合体在 NSG-HCD34系统概括了类似于神经hiv的人的神经炎症的关键方面。该提案综合目的的基础假设的测试将确定哪些剪接变体 OPN/SPP1的活动中有效增加小胶质细胞和特定神经元亚型的神经炎症信号传导，这些反应是如何的受监管以及认知或情感行为是否发生了改变。