Role of Gut Microbiome- Brain Axis in Modulating CNS Inflammasomes in the Neuropathology Produced by Opioid Exposure and HIV
肠道微生物组-脑轴在阿片类药物暴露和 HIV 产生的神经病理学中调节中枢神经系统炎症小体的作用
基本信息
- 批准号:10020183
- 负责人:
- 金额:$ 37.97万
- 依托单位:
- 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 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAlcohol or Other Drugs useAnimalsAntibioticsAttentionAttenuatedBacterial TranslocationBindingBiologicalBrainBreedingCellsChronicComplexDataDevelopmentDiseaseDisease ProgressionDrug abuseDrug usageDrug userEndotoxinsEnterococcus faecalisExtravasationFirmicutesFunctional disorderGenesGerm-FreeGram-Negative BacteriaGram-Positive BacteriaHIVHIV Envelope Protein gp120HIV InfectionsHIV-1ImmuneImmune systemIndividualInfectionInflammasomeInflammationInflammation MediatorsInflammatoryInflammatory ResponseLeadLeaky GutLigandsLoxP-flanked alleleMicrogliaModelingMolecularMorphineMusNeurocognitiveNeuropathogenesisOpiate AddictionOpioidPatientsPatternPredispositionPrevalenceProbioticsProductionProteinsRibosomesRodent ModelRoleSignal PathwaySignal TransductionTLR2 geneTestingTissuesToll-like receptorsbacterial communitycytokinedrug abuserdysbiosisgut microbiomegut microbiotamarenostrinmicrobialmicrobiotaneurocognitive disorderneuroinflammationneuropathologyopioid abuseopioid exposureopioid usepathogenreceptorsex
项目摘要
Abstract/Project Summary
Chronic opioid use is associated with gut microbial dysbiosis, gut barrier disruption and systemic bacterial
translocation. Gut leakiness, microbial translocation and systemic inflammation are hallmarks of HIV disease
progression. In recent years, much attention has been focused towards elucidating the impact of Toll-like
receptors (TLRs) in microglial activation and NLRP3 inflammasome assembly as a mechanism for sustained
neuroinflammation and neurocognitive disease progression. While previous studies have investigated the
direct effect of HIV associated toxic proteins (TAT and gp120) and opioids on inflammasome activation on
microglial little is known about the role of gut derived products and their impact on inflammasome activation
and neurocognitive disorders that are prevalent in substance using HIV patients. Although most studies
correlate endotoxin levels and bacterial products derived from gram-negative bacteria with inflammation and
HIV disease progression, recent studies clearly show a distinct enrichment and prevalence of gram positive
bacterial communities in HIV infected patients when compared to normal healthy individuals. Our central
hypothesis is that microbial dysbiosis with predominant expansion of Gram positive bacterial communities
leading to systemic leakage of G+ bacterial products serve as cognate ligands on TLR2 on microglial cells
leading to TLR2 activation and induction of inflammasome components assembly. Our central hypothesis is
supported by the following preliminary data. Using a rodent model of HIV in the context of drug abuse, we
demonstrate 1) Significant increase in a) gut bacterial translocation b) systemic inflammation c) NLRP3
expression on microglial cells in HIV infected animals that are dramatically exacerbated in HIV+ Morphine
treated animals when compared to their respective controls. 2) Morphine induced NLRP3 expression is only
observed in the presence of TLR2 cognate ligand in BV2 microglial cells. We will test the hypothesis that gut-
microbiota immune brain axis activate inflammasome signaling pathways in brain microglial cells leading to
sustained inflammation contributing to the neuropathology of HAND in an opioid abusing HIV infected patients.
Aim 1: We will establish the role of the gut microbiota in microglial inflammasome activation using a) germ free
mice b) differential antibiotic (gram specific depletion)treated mice and c) infection with gram positive
Enterococcus Faecalis. We will also investigate if sex of the animals serves as a biological variable in microglia
NLRP3 activation in our model of opioid dependence in the context of HIV infection. Aim 2: Determine the role
of TLR2 in NLRP3 induction in microglial cells using tissue specific deletion by breeding floxed TLR2 with
microglial specific cre expression using Cx3Cr1 Cre mice. Aim 3: Determine if combination of probiotics and
TLR2 antagonist attenuate NLRP3 induction on microglial cells.
摘要/项目摘要
慢性阿片类药物使用与肠道微生物生态失调、肠道屏障破坏和全身性细菌感染有关。
易位肠道渗漏、微生物移位和全身炎症是艾滋病的标志
进展近年来,许多注意力已经集中在阐明Toll样的影响上,
受体(TLR)在小胶质细胞活化和NLRP 3炎性体组装中作为持续性炎症反应的机制。
神经炎症和神经认知疾病进展。虽然以前的研究已经调查了
HIV相关毒性蛋白(达特和gp 120)和阿片类药物对炎性小体激活的直接作用
小胶质细胞的肠源性产物的作用及其对炎性小体激活的影响知之甚少
和神经认知障碍,这些疾病在使用药物的艾滋病患者中普遍存在。虽然大多数研究
将内毒素水平和来自革兰氏阴性菌的细菌产物与炎症相关联,
艾滋病毒疾病的进展,最近的研究清楚地表明,一个明显的富集和流行的革兰氏阳性
HIV感染者的细菌群落与正常健康个体相比。我们的中央
假设是微生物生态失调,其中革兰氏阳性细菌群落占优势
导致G+细菌产物作为小胶质细胞上TLR 2的同源配体的系统性渗漏
导致TLR 2活化和诱导炎性小体组分组装。我们的核心假设是
由以下初步数据支持。在药物滥用的背景下使用啮齿动物HIV模型,我们
证明1)a)肠道细菌易位B)全身性炎症c)NLRP 3的显著增加
在HIV感染的动物中小胶质细胞上的表达在HIV+吗啡中显著加剧
与其各自的对照相比,给药动物。2)吗啡诱导的NLRP 3表达仅为
在BV 2小胶质细胞中存在TLR 2同源配体时观察到。我们将检验直觉-
微生物群免疫脑轴激活脑小胶质细胞中的炎性体信号通路,
持续的炎症导致阿片类药物滥用HIV感染患者的HAND神经病理学。
目的1:我们将使用a)无菌的
小鼠B)差异抗生素(革兰氏特异性耗竭)处理的小鼠和c)革兰氏阳性菌感染
粪肠球菌我们还将研究动物的性别是否作为小胶质细胞的生物学变量
NLRP 3在我们的阿片类药物依赖模型中的激活在HIV感染的背景下。目标2:确定角色
使用组织特异性缺失,通过将floxed TLR 2与
使用Cx 3Cr 1 Cre小鼠的小胶质细胞特异性cre表达。目的3:确定益生菌和
TLR 2拮抗剂减弱小胶质细胞上的NLRP 3诱导。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sabita Roy其他文献
Sabita Roy的其他文献
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{{ truncateString('Sabita Roy', 18)}}的其他基金
(PQ6) Mesenchymal stem cell based and immunocompetent mouse models of HIV/AIDS KSHV-driven sarcomagenesis
(PQ6) 基于间充质干细胞和免疫活性的 HIV/AIDS 小鼠模型 KSHV 驱动的肉瘤发生
- 批准号:
10388236 - 财政年份:2021
- 资助金额:
$ 37.97万 - 项目类别:
(PQ6) Mesenchymal stem cell based and immunocompetent mouse models of HIV/AIDS KSHV-driven sarcomagenesis
(PQ6) 基于间充质干细胞和免疫活性的 HIV/AIDS 小鼠模型 KSHV 驱动的肉瘤发生
- 批准号:
10609000 - 财政年份:2021
- 资助金额:
$ 37.97万 - 项目类别:
Role of Gut Microbiome- Brain Axis in Modulating CNS Inflammasomes in the Neuropathology Produced by Opioid Exposure and HIV
肠道微生物组-脑轴在阿片类药物暴露和 HIV 产生的神经病理学中调节中枢神经系统炎症小体的作用
- 批准号:
10434855 - 财政年份:2019
- 资助金额:
$ 37.97万 - 项目类别:
Multidisciplinary Training in Substance Abuse Research
药物滥用研究的多学科培训
- 批准号:
10395444 - 财政年份:2019
- 资助金额:
$ 37.97万 - 项目类别:
Role of Gut Microbiome- Brain Axis in Modulating CNS Inflammasomes in the Neuropathology Produced by Opioid Exposure and HIV
肠道微生物组-脑轴在阿片类药物暴露和 HIV 产生的神经病理学中调节中枢神经系统炎症小体的作用
- 批准号:
10434466 - 财政年份:2019
- 资助金额:
$ 37.97万 - 项目类别:
Role of Gut Microbiome- Brain Axis in Modulating CNS Inflammasomes in the Neuropathology Produced by Opioid Exposure and HIV
肠道微生物组-脑轴在阿片类药物暴露和 HIV 产生的神经病理学中调节中枢神经系统炎症小体的作用
- 批准号:
10518777 - 财政年份:2019
- 资助金额:
$ 37.97万 - 项目类别:
Role of Gut Microbiome- Brain Axis in Modulating CNS Inflammasomes in the Neuropathology Produced by Opioid Exposure and HIV
肠道微生物组-脑轴在阿片类药物暴露和 HIV 产生的神经病理学中调节中枢神经系统炎症小体的作用
- 批准号:
10653501 - 财政年份:2019
- 资助金额:
$ 37.97万 - 项目类别:
Role of Gut Microbiome- Brain Axis in Modulating CNS Inflammasomes in the Neuropathology Produced by Opioid Exposure and HIV
肠道微生物组-脑轴在阿片类药物暴露和 HIV 产生的神经病理学中调节中枢神经系统炎症小体的作用
- 批准号:
10754697 - 财政年份:2019
- 资助金额:
$ 37.97万 - 项目类别:
Role of Gut Microbiome- Brain Axis in Modulating CNS Inflammasomes in the Neuropathology Produced by Opioid Exposure and HIV
肠道微生物组-脑轴在阿片类药物暴露和 HIV 产生的神经病理学中调节中枢神经系统炎症小体的作用
- 批准号:
10197088 - 财政年份:2019
- 资助金额:
$ 37.97万 - 项目类别:
Multidisciplinary Training in Substance Abuse Research
药物滥用研究的多学科培训
- 批准号:
9919533 - 财政年份:2019
- 资助金额:
$ 37.97万 - 项目类别: