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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：
10560338
负责人：
AMANDA MARIA BROWN
金额：
$ 74.11万
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/10560338
关键词：
Adult Affective Aging Autopsy Basal Ganglia Behavior Biochemical Brain Buffers Cells Cerebellum Cerebral Ventricles Chemotactic Factors Chimera organism Chronic Cognition Cognitive Corpus striatum structure Detection Development Experimental Models Flow Cytometry Genetic Transcription Goals Gold HIV HIV Infections Homeostasis Human ITGB3 gene Immune In Vitro Incidence Infection Inflammation Injury Integrins Investigation Ligands Liver Lung Magnetic Resonance Imaging Mammals Measures Microglia Modification Molecular Molecular Mechanisms of Action 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 macrophage microPET monocyte mouse model neuroAIDS neuroimaging neuroinflammation 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.

项目总结