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:10612386
- 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 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAmericanAstrocytesBlood - brain barrier anatomyBrainBrain InjuriesCCL2 geneCD14 geneCD4 Positive T LymphocytesCell SeparationCellsCentral Nervous System DiseasesCentral Nervous System InfectionsChronicCognitive deficitsDevelopmentDiseaseEnhancersExposure toFCGR3B geneGene ExpressionGenesGenetic TechniquesGoalsHIVHIV InfectionsHIV SeropositivityHIV therapyHeroinHumanImpaired cognitionIn VitroIndividualInfectionInflammationInflammatoryInterventionLengthMacrophageMacrophage ActivationMediatingMediatorMicrogliaModelingMolecularMorphineMusNational NeuroAids Tissue ConsortiumNeuronal DysfunctionNeuronsNeuropathogenesisOpioidOpioid ReceptorPalliative CarePathway interactionsPatternPeripheralPersonsPlasmaProcessProductionProductivityProteinsProvirusesQuality of lifeSignal PathwaySubstance Use DisorderSubstance abuse problemTechniquesTherapeuticTransgenic MiceTransgenic OrganismsViralViral ProteinsViremiaVirusantiretroviral therapyblood-brain barrier crossingbrain endothelial cellchemokinecognitive functioncyclin T1cytokineexcitotoxicityhuman migrationimmune activationimprovedin vivoinnovationmigrationmonocytemouse modelneuroinflammationopioid abuseopioid useopioid userpalliativeperipheral bloodprescription opioidpromotersingle-cell RNA sequencingsynergismtherapeutic 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.
本研究旨在探讨hiv介导的神经炎症的分子机制
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:
9919529 - 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:
9407532 - 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:
9915978 - 财政年份:2017
- 资助金额:
$ 83.41万 - 项目类别:
ERC Einstein Rockefeller CUNY Center for AIDS Research
ERC 爱因斯坦洛克菲勒纽约市立大学艾滋病研究中心
- 批准号:
10605270 - 财政年份:2017
- 资助金额:
$ 83.41万 - 项目类别:
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