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.

摘要：母基金 (DA050545) 重点评估小胶质细胞炎症体 NLRP3 在由于艾滋病毒感染者（PLWH）是由艾滋病毒和可卡因使用介导的神经炎症。由于有效的组合抗逆转录病毒药物，现在人们的寿命更长了，因此毫不奇怪，有一种与年龄相关的合并症的激增与已经存在的 HAND 症状相交叉鉴于此，前者的过早衰老和阿尔茨海默氏症样表型有所增加。在 PLWH 中有意义，根据临床发现，我们实验室的研究也证明了有毒淀粉样蛋白沉积物在感染 SIV 的猕猴以及其他猕猴的大脑切片中积累来自接触可卡因的 HAND 患者（来自 NNTC）以及接触可卡因的 HIV 转基因大鼠的大脑此外，在我们最近报道的细胞培养研究中，我们还发现了可卡因。由 HIV Tat 激活的小胶质细胞产生的激活的 NLRP3 炎性体可以穿梭到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 导致综上所述，我们发现神经元中有毒淀粉样蛋白的表达上调。 Tat 和可卡因介导的小胶质细胞 NLRP3 激活（亲本资助）可以通过小胶质细胞穿梭 EVs到达受体神经元以诱导有毒的淀粉样蛋白和衰老介质，这反过来又可能是在从血浆中分离出的富含神经的 EV 中被检测为生物标志物。虽然家长资助的重点旨在了解激活的 NLRP3 炎性体在 HIV Tat 和可卡因（可卡因）背景下的作用补充品旨在将这些研究扩展到现有的、已存档的群体血浆和大脑样本对感染 SIV 的恒河猴施用/不施用可卡因以评估淀粉样蛋白病理学我们将研究这些动物大脑中的衰老表型和血浆中的脑源性神经元 EV。还将大脑中小胶质细胞 NLRP3 的表达与血浆富集的小胶质细胞 EV 中的 NLRP3 相关联以及富含血浆的神经元 EV 中衰老/AD 货物的表达水平。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NLRP3 Inflammasome Blockade Reduces Cocaine-Induced Microglial Activation and Neuroinflammation.

NLRP3 炎症小体阻断可减少可卡因诱导的小胶质细胞激活和神经炎症。

DOI：
发表时间：
2021-05
期刊：
影响因子：
5.1
作者：
Chivero, Ernest T;Thangaraj, Annadurai;Tripathi, Ashutosh;Periyasamy, Palsamy;Guo, Ming;Buch, Shilpa
通讯作者：
Buch, Shilpa

Protective Role of Lactobacillus rhamnosus Probiotic in Reversing Cocaine-Induced Oxidative Stress, Glial Activation and Locomotion in Mice.

鼠李糖乳杆菌益生菌在逆转可卡因诱导的氧化应激、神经胶质激活和小鼠运动中的保护作用。

DOI：
发表时间：
2022-06
期刊：
影响因子：
0
作者：
Chivero, Ernest T;Sil, Susmita;Singh, Seema;Thangaraj, Annadurai;Gordon, Lila;Evah;Ferguson, Natasha;Callen, Shannon;Buch, Shilpa
通讯作者：
Buch, Shilpa

Role of Dysregulated Autophagy in HIV Tat, Cocaine, and cART Mediated NLRP3 Activation in Microglia.

自噬失调在 HIV Tat、可卡因和 cART 介导的小胶质细胞中 NLRP3 激活中的作用。