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Molecular mechanisms underlying HIV & Cocaine-mediated microglial activation: Targeting NLRP3 inflammasome

HIV的分子机制

基本信息

批准号：
10846423
负责人：
Shilpa J. Buch
金额：
$ 38.38万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10846423
关键词：
Acceleration Address Administrative Supplement Affect Aging Alzheimer&apos s Disease Amyloid Amyloid Proteins Amyloid beta-Protein Animals Anti-Retroviral Agents Archives Basal Ganglia Biological Markers Brain Brain region Cell Culture Techniques Chest Clinical Cocaine Cocaine Dependence DNA Methylation Data Deposition Disease Freezing Goals HIV HIV Infections HIV-associated neurocognitive disorder Hippocampus Immune Impaired cognition Individual Infection Inflammasome Lead Light Link Longevity Macaca Macaca mulatta Mediating Mediator Messenger RNA MicroRNAs Microglia Modeling Molecular Monkeys Neurocognitive Deficit Neurons Paraffin Pathogenesis Pathology Patients Peripheral Persons Phenotype Plasma Premature aging syndrome Prevalence Proteins Publishing Quality of life RNA Rat Transgene Recovery Reporting Residual state Rodent Role SIV Saline Sampling Signal Transduction Substance Use Disorder Symptoms Synapses Testing Untranslated RNA Viral Viral Proteins Viremia age related age related neurodegeneration aged aging brain amyloid pathology antiretroviral therapy biomarker identification brain tissue cocaine exposure cocaine use combinatorial comorbidity epidemiologic data extracellular vesicles frontal lobe glial activation human data improved male neurocognitive disorder neuroinflammation nonhuman primate novel parent grant peripheral blood senescence symptomatology tau Proteins tau-1

项目摘要

Summary: The parent grant (DA050545) focuses on assessing the role of microglial inflammasome NLRP3 in the context of neuroinflammation mediated by HIV and cocaine use. Since people living with HIV (PLWH) are now enjoying longer life-span, owing to effective combinatorial antiretrovirals, it is no surprise that there is an emerging surge of age-related comorbidities intersecting with the already existent HAND symptomatology in these individuals. In light of this, clinicians are seeing a rise in premature aging and Alzheimer’s-like phenotype in PLWH. Interestingly, in keeping with the clinical findings, studies from our lab have also demonstrated the accumulation of toxic amyloid deposits in the sections of brains from SIV-infected macaques as well as those from HAND patients with cocaine exposure (from NNTC) and, in the brains of HIV Transgenic rats exposed to cocaine (preliminary studies). Furthermore, in our recently reported cell culture study, we have also demonstrated that activated NLRP3 inflammasome generated from HIV Tat-activated microglia can shuttle to the bystander neurons via the extracellular vesicles (EVs), and unpublished data showed these EVs lead to upregulated expression of toxic amyloid proteins in the neurons. Taken together, we thus hypothesize that HIV Tat and cocaine-mediated activation of microglial NLRP3 (parent grant) could be shuttled through the microglial EVs to the recipient neurons to induce toxic amyloids and senescence mediators, which, in turn, could be detected as biomarkers in neuronal enriched EVs isolated from the plasma. While the focus of the parent grant is on understanding the role of activated NLRP3 inflammasome in the context of HIV Tat, and cocaine, the supplement aims to extend these studies to already available, archived plasma and brain samples from groups of SIV-infected rhesus macaques administered with/without cocaine for assessing the amyloid pathology and senescence phenotype in the brains of these animals and brain-derived neuronal EVs in the plasma. We will also correlate the expression of microglial NLRP3 in the brain with NLRP3 in plasma-enriched microglial EVs and expression levels of aging/AD cargos in the plasma-enriched neuronal EVs.

概述：母基金（DA 050545）专注于评估小胶质细胞炎性小体NLRP 3在 HIV和可卡因使用介导的神经炎症的背景。由于艾滋病毒感染者（PLWH）由于有效的组合抗逆转录病毒药物，现在享有更长的寿命，年龄相关合并症的出现激增，与已经存在的手部疾病交叉，这些人。有鉴于此，临床医生看到了过早衰老和阿尔茨海默氏症样表型的增加在PLWH。有趣的是，与临床发现一致，我们实验室的研究也证明了在SIV感染的猕猴脑切片中，在接触可卡因的HAND患者（来自NNTC）和接触可卡因的HIV转基因大鼠的大脑中，可卡因（初步研究）。此外，在我们最近报道的细胞培养研究中，我们还证明了由HIV Tat激活的小胶质细胞产生的激活的NLRP 3炎性体可以穿梭于旁观者神经元通过细胞外囊泡（EV），未发表的数据显示这些EV导致上调神经元中毒性淀粉样蛋白的表达。综上所述，我们假设艾滋病毒达特和可卡因介导的小胶质细胞NLRP 3（亲本）的激活可以穿梭于小胶质细胞中。 EV对受体神经元诱导毒性淀粉样蛋白和衰老介质，这反过来，在从血浆中分离的神经元富集EV中检测为生物标志物。虽然父母补助金的重点是是了解激活的NLRP 3炎性体在HIV达特和可卡因背景下的作用，一个补充的目的是将这些研究扩展到已经可用的，存档的血浆和大脑样本， SIV感染的恒河猴与/不与可卡因给药，以评估淀粉样蛋白病理学，这些动物脑中的衰老表型和血浆中的脑源性神经元EV。我们将还将脑中小胶质细胞NLRP 3的表达与血浆富集的小胶质细胞EV中的NLRP 3相关联和血浆富集的神经元EV中衰老/AD货物的表达水平。