Mechanisms of opioid- mediated HIV neuropathogenesis
阿片类药物介导的 HIV 神经发病机制
基本信息
- 批准号:9919529
- 负责人:
- 金额:$ 83.41万
- 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:2019-05-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AmericanAstrocytesBlood - brain barrier anatomyBrainBrain InjuriesCCL2 geneCD14 geneCD4 Positive T LymphocytesCellsCentral Nervous System DiseasesCentral Nervous System InfectionsChronicCognitive deficitsDevelopmentDiseaseEnhancersExposure toFCGR3B geneFunctional disorderGene ExpressionGenesGenetic TechniquesGoalsHIVHIV InfectionsHIV SeropositivityHIV antiretroviralHIV therapyHeroinHumanImpaired cognitionIn VitroIndividualInfectionInflammationInflammatoryInterventionLengthMacrophage ActivationMediatingMediator of activation proteinMicrogliaModelingMolecularMorphineMusNational NeuroAids Tissue ConsortiumNeuronsNeuropathogenesisOpioidOpioid ReceptorPalliative CarePathway interactionsPatternPeripheralPlasmaProcessProductionProteinsProvirusesQuality of lifeSeedsSignal PathwaySubstance Use DisorderSubstance abuse problemTechniquesTherapeuticTransgenic MiceTransgenic OrganismsViralViral ProteinsViremiaVirusantiretroviral therapybrain endothelial cellchemokinecognitive functioncyclin T1cytokineexcitotoxicityimmune activationimprovedin vivoinnovationmacrophagemigrationmonocytemouse modelneuroinflammationopioid abuseopioid useopioid userpalliativeperipheral bloodprescription opioidpromotersingle-cell RNA sequencingtherapeutic targettissue culturetranscriptome
项目摘要
This proposal is to examine molecular mechanisms of HIV-mediated neuroinflammation in the presence of
ART and opiods. We will use morphine as it exacerbates inflammation and CNS disease in many HIV infected
people. HIV infection of the CNS results in chronic inflammation that leads to cognitive deficits in > 50% of
infected people. This inflammation and subsequent CNS damage is not mitigated with ART. Inflammation is a
key process in HIV disease and therapies to limit this and ongoing CNS viral seeding must be developed to
improve the quality of life of infected people. This is even more pressing as HIV positive people live longer. HIV
enters the CNS soon after peripheral infection and despite ART, persists within infected cells. HIV entry into
the brain is mediated, at least in part, by infected monocyte transmigration across the blood brain barrier
(BBB). Mature monocytes expressing CD14 and CD16 are key mediators of HIV neuropathogenesis. These
monocytes are productively infected with HIV and primed to cross the BBB. Once within the CNS, they may
differentiate into infected macrophages that can persist for years. This leads to infection and/or activation of
CNS cells, including macrophages and microglia, resulting in chronic inflammation characterized by production
of virus and/or viral proteins, and cytokines, and chemokines. Chemokines, in particular CCL2, increase
transmigration of peripheral blood infected/uninfected monocytes, continuing inflammation and viral seeding of
the CNS that mediates neuronal dendritic pruning and degeneration in a large number of infected people by
mechanisms not well understood. ART does not eliminate cells harboring HIV. Thus, monocyte/macrophage
activation, and production of HIV early proteins continue, resulting in brain injury despite successful ART. We
will characterize effects of morphine, HIV, and ART on mechanisms that mediate monocyte entry into the CNS
and on subsequent viral reseeding and neuroinflammation. We will use state of the art in vitro techniques, the
powerful approach of single cell RNA sequencing, and transgenic mice to characterize potential therapeutics to
limit inflammation and guide efficacy of ART. We will characterize the impact of morphine and ART on
transmigration of HIV infected and uninfected human monocytes across a model of the human BBB and use
scRNA-seq to identify unique genes expressed by individual transmigrating HIV-infected and HIV-exposed
monocytes in the presence or absence of morphine; characterize the impact of HIV, ART, and/or morphine on
the function of human macrophages and, using scRNA-seq, on expression of inflammatory genes by individual
human macrophages; apply an HIV transgenic mouse model to evaluate the in vivo impact of opioids and HIV
on inflammatory genes expressed in vivo by individual monocytes from the mice that transmigrated across the
BBB, and by resident individual brain macrophages/microglia from these mice; and compare expression of
inflammatory genes by individual macrophages/microglia isolated from the brains of HIV-naïve and HIV-
infected individuals including those from people who were on palliative opioid treatment using scRNA-seq.
该提案旨在研究存在 HIV 的情况下 HIV 介导的神经炎症的分子机制
ART 和阿片类药物。我们将使用吗啡,因为它会加剧许多艾滋病毒感染者的炎症和中枢神经系统疾病
人们。中枢神经系统的 HIV 感染会导致慢性炎症,导致 50% 以上的人出现认知缺陷
感染人群。 ART 无法减轻这种炎症和随后的中枢神经系统损伤。炎症是一种
必须开发艾滋病毒疾病和限制这种情况的治疗方法以及正在进行的中枢神经系统病毒播种的关键过程,以
改善感染者的生活质量。随着艾滋病毒呈阳性的人寿命更长,这一问题变得更加紧迫。艾滋病病毒
外周感染后不久就进入中枢神经系统,尽管进行了抗逆转录病毒治疗,但仍持续存在于受感染的细胞内。 HIV进入
大脑至少部分是由受感染的单核细胞跨血脑屏障的迁移介导的
(BBB)。表达 CD14 和 CD16 的成熟单核细胞是 HIV 神经发病的关键介质。这些
单核细胞有效地感染艾滋病毒并准备好穿过血脑屏障。一旦进入中枢神经系统,他们可能
分化为可持续数年的受感染巨噬细胞。这会导致感染和/或激活
中枢神经系统细胞,包括巨噬细胞和小胶质细胞,导致慢性炎症,其特征是产生
病毒和/或病毒蛋白、细胞因子和趋化因子。趋化因子,特别是 CCL2,增加
外周血感染/未感染的单核细胞的迁移,持续的炎症和病毒播种
中枢神经系统介导大量感染者的神经元树突修剪和变性
机制尚不清楚。 ART 并不能消除携带 HIV 的细胞。因此,单核细胞/巨噬细胞
尽管抗逆转录病毒疗法取得了成功,但艾滋病毒早期蛋白质的激活和产生仍在继续,导致脑损伤。我们
将描述吗啡、HIV 和 ART 对介导单核细胞进入中枢神经系统机制的影响
以及随后的病毒重新播种和神经炎症。我们将使用最先进的体外技术,
单细胞 RNA 测序和转基因小鼠的强大方法来表征潜在的治疗方法
限制炎症并指导 ART 的疗效。我们将描述吗啡和 ART 对
HIV感染和未感染的人类单核细胞在人类BBB模型中的迁移和使用
scRNA-seq 用于识别 HIV 感染者和 HIV 暴露者所表达的独特基因
在存在或不存在吗啡的情况下的单核细胞;描述 HIV、ART 和/或吗啡对
人类巨噬细胞的功能,并使用 scRNA-seq 来研究个体炎症基因的表达
人类巨噬细胞;应用 HIV 转基因小鼠模型评估阿片类药物和 HIV 的体内影响
对来自小鼠的单个单核细胞在体内表达的炎症基因的影响
BBB,以及来自这些小鼠的常驻个体大脑巨噬细胞/小胶质细胞;并比较表达式
从未感染艾滋病毒和艾滋病毒感染者的大脑中分离出的单个巨噬细胞/小胶质细胞的炎症基因
感染者,包括使用 scRNA-seq 接受姑息性阿片类药物治疗的人。
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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Joan Weinberger Berman其他文献
Joan Weinberger Berman的其他文献
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{{ truncateString('Joan Weinberger Berman', 18)}}的其他基金
The impact of methamphetamine on CXCL12 mediated HIV neuropathogenesis
甲基苯丙胺对 CXCL12 介导的 HIV 神经发病机制的影响
- 批准号:
10547875 - 财政年份:2022
- 资助金额:
$ 83.41万 - 项目类别:
Inflammation, BBB disruption, and Reward Function in the Pathogenesis of Depression among PWH
感染者抑郁症发病机制中的炎症、血脑屏障破坏和奖赏功能
- 批准号:
10535898 - 财政年份:2022
- 资助金额:
$ 83.41万 - 项目类别:
The impact of methamphetamine on CXCL12 mediated HIV neuropathogenesis
甲基苯丙胺对 CXCL12 介导的 HIV 神经发病机制的影响
- 批准号:
10666675 - 财政年份:2022
- 资助金额:
$ 83.41万 - 项目类别:
Inflammation, BBB disruption, and Reward Function in the Pathogenesis of Depression among PWH
感染者抑郁症发病机制中的炎症、血脑屏障破坏和奖赏功能
- 批准号:
10707230 - 财政年份:2022
- 资助金额:
$ 83.41万 - 项目类别:
Mechanisms of opioid- mediated HIV neuropathogenesis
阿片类药物介导的 HIV 神经发病机制
- 批准号:
10383747 - 财政年份:2019
- 资助金额:
$ 83.41万 - 项目类别:
Mechanisms of opioid- mediated HIV neuropathogenesis
阿片类药物介导的 HIV 神经发病机制
- 批准号:
9767913 - 财政年份:2019
- 资助金额:
$ 83.41万 - 项目类别:
Mechanisms of opioid- mediated HIV neuropathogenesis
阿片类药物介导的 HIV 神经发病机制
- 批准号:
10612386 - 财政年份:2019
- 资助金额:
$ 83.41万 - 项目类别:
Monocyte CNS HIV entry & neurodegeneration: Translational studies in the CART era
单核细胞 CNS HIV 进入
- 批准号:
9915978 - 财政年份:2017
- 资助金额:
$ 83.41万 - 项目类别:
Effect of buprenorphine on monocytes in the context of neuroAids and opioid abuse
神经辅助药物和阿片类药物滥用中丁丙诺啡对单核细胞的影响
- 批准号:
10618101 - 财政年份:2017
- 资助金额:
$ 83.41万 - 项目类别:
Monocyte CNS HIV entry & neurodegeneration: Translational studies in the CART era
单核细胞 CNS HIV 进入
- 批准号:
9407532 - 财政年份:2017
- 资助金额:
$ 83.41万 - 项目类别:
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