DAT-Psychostimulant mediated dopamine release increases macrophage IL-1beta production through NF-kB activation and inflammasome priming
DAT 精神兴奋剂介导的多巴胺释放通过 NF-kB 激活和炎症小体引发增加巨噬细胞 IL-1β 的产生
基本信息
- 批准号:9978381
- 负责人:
- 金额:$ 23.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectB-Cell ActivationBehaviorBindingBiological Response ModifiersBrainBrain regionCXCL10 geneCellsCentral Nervous System AgentsCentral Nervous System DiseasesCerebrovascular DisordersCocaineCocaine AbuseComplexCorpus striatum structureDataDevelopmentDopamineDopamine ReceptorDrug abuseDrug usageEnhancersExposure toFutureGene ExpressionGene ProteinsGenesHIVHealthHepatitis C virusHumanIKK alphaIL8 geneImageImmuneIncidenceInfectionInflammasomeInflammationInflammation MediatorsInflammatoryInflammatory ResponseInterleukin-1 betaInterleukin-6KineticsLeukocytesLightLinkMAP3K7 geneMaintenanceMediatingMethamphetamineMicroarray AnalysisMicrogliaMolecularMultiprotein ComplexesMyelogenousMyeloid CellsNF-kappa BNerve DegenerationNeuraxisNeurodegenerative DisordersNuclearNuclear TranslocationNucleus AccumbensOutcomePathway interactionsPharmaceutical PreparationsPhosphotransferasesPopulationPrefrontal CortexProductionProteinsPublishingResearchRiskRodent ModelRoleSignal TransductionSmall Interfering RNAStimulusSystemTechniquesTherapeuticTranscriptional ActivationWestern Blottingaddictionchromatin immunoprecipitationcocaine usecytokinedopamine systemdrug abuserexperimental studyextracellularimprovedknock-downmacrophagemarenostrinmethamphetamine usemonocytemotor disordernervous system disorderneuroinflammationneuropathologyneuropsychiatric disordernon-drugnovelpathogenic bacteriapreventpsychostimulantreceptorrecruitresponsescaffoldstimulant abusestimulant usetherapeutic targettranscription factor
项目摘要
DAT18-01. Abuse of stimulants, such as cocaine and methamphetamine, results in a variety of
serious health conditions, and drug abusers have poorer health outcomes than non-drug using,
demographically similar populations. In the central nervous system, the use of stimulants induces
neuroinflammation through a greater release of inflammatory factors and recruitment of additional
leukocytes. This predisposes drug abusers to a higher incidence of neuropsychiatric,
cerebrovascular and motor disorders, and can also exacerbate the neuropathogenic impact of
infection with HIV, HCV and a number of bacterial pathogens. The precise pathways by which
stimulants mediate these effects are not clear, but many of these effects could be induced by
drug-associated activation of specific inflammatory triggers such as NF- kB. However, direct links
between stimulants and these neuroinflammatory mechanisms have not been described. The
premise of this proposal is that dopamine acts as a common mechanism by which
stimulants activate myeloid cell NF-kB and thereby initiate or exacerbate
neuroinflammation. Use of all stimulants acutely increases CNS dopamine levels, exposing cells
in dopamine-rich brain regions to aberrantly high dopamine concentrations. Among these cell
populations are myeloid cells, such as perivascular macrophages and microglia, which are the
primary immune cells in the CNS. Our published research shows that acute exposure to elevated
dopamine increases myeloid production of inflammatory cytokines, such as IL-1b, IL-6, CXCL8
and CXCL10. Our preliminary data suggest that dopamine acts by activating the NF- kB pathway
and priming the NLRP3 inflammasome, a complex that regulates the release of IL-1b, a master
regulator of inflammation. The specific pathways mediating this effect are not clear, and therefore
these studies will generate detailed information about specific dopamine receptors, gene and
protein targets mediating dopamine activation of
NF-kB
and NLRP3 in human macrophages.
Determining the specific signaling mechanisms and genes involved in dopamine induced
increases in NF-kB activity will indicate pathways that could be targeted to ameliorate the
neuroinflammatory effects of stimulant use, significantly improving the long-term health outcomes
of stimulant users. The data developed in this proposal will serve as a basis for future projects
examining the modulation of the myeloid dopaminergic system as a therapeutic strategy for
limiting the increased incidence of neurologic disease and inflammation associated with drug
abuse. These projects will examine both novel effectors and the repurposing of existing
dopaminergic therapeutics to ameliorate inflammation in the stimulant abusing population.
DAT18-01。滥用兴奋剂,如可卡因和甲基苯丙胺,导致各种
严重的健康状况,吸毒者的健康结果比不吸毒者更差,
人口统计上相似的人群。在中枢神经系统中,兴奋剂的使用会诱导
通过更大程度地释放炎症因子和招募更多的
白细胞。这使吸毒者容易患上更高的神经精神疾病,
脑血管和运动障碍,也可加剧神经致病的影响
感染艾滋病毒、丙型肝炎病毒和一些细菌病原体。准确的路径,通过它
兴奋剂介导这些效应尚不清楚,但许多这些效应可能是由
药物相关的特定炎症因子的激活,如核因子-kB。然而,直接联系
兴奋剂和这些神经炎症机制之间的关系还没有被描述。这个
这一提议的前提是多巴胺作为一种共同的机制
兴奋剂激活髓系细胞核因子-kB,从而启动或加剧
神经炎。所有兴奋剂的使用都会显著增加中枢多巴胺水平,使细胞暴露
在多巴胺丰富的大脑区域,导致异常高的多巴胺浓度。在这些细胞中
人群是髓系细胞,如血管周围巨噬细胞和小胶质细胞,这是
中枢神经系统中的初级免疫细胞。我们发表的研究表明,急性暴露于高水平的
多巴胺促进髓系细胞产生炎性细胞因子,如IL-1b、IL-6、CXCL8
和CXCL10。我们的初步数据表明,多巴胺通过激活核因子-kB途径发挥作用
并启动NLRP3炎症体,这是一种调节IL-1b释放的复合体,是一种主要的
炎症调节剂。调节这一效应的具体途径尚不清楚,因此
这些研究将产生关于特定多巴胺受体、基因和
介导多巴胺激活的蛋白质靶点
核因子-kB
和NLRP3在人巨噬细胞中的表达。
确定多巴胺诱导的特定信号机制和基因
核因子-kB活性的增加将表明可以靶向改善
使用兴奋剂的神经炎症效应,显著改善长期健康结果
兴奋剂使用者。本提案中开发的数据将作为未来项目的基础
研究髓系多巴胺能系统的调节作为一种治疗策略
限制与药物有关的神经系统疾病和炎症的增加
虐待。这些项目将研究新的效应器和现有的
多巴胺能疗法减轻兴奋剂滥用人群的炎症反应。
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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Peter Jesse Gaskill其他文献
Peter Jesse Gaskill的其他文献
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{{ truncateString('Peter Jesse Gaskill', 18)}}的其他基金
Defining molecular mechanisms by which stimulant evoked dopamine drives inflammation and neuronal dysfunction in neuroHIV
定义兴奋剂诱发多巴胺驱动神经艾滋病毒炎症和神经元功能障碍的分子机制
- 批准号:
10685160 - 财政年份:2023
- 资助金额:
$ 23.48万 - 项目类别:
Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations
苯二氮卓介导离散骨髓细胞群转录半静止机制
- 批准号:
10700122 - 财政年份:2022
- 资助金额:
$ 23.48万 - 项目类别:
Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations
苯二氮卓介导离散骨髓细胞群转录半静止机制
- 批准号:
10573380 - 财政年份:2022
- 资助金额:
$ 23.48万 - 项目类别:
Mechanisms of dopamine mediated increase in HIV infection of macrophages
多巴胺介导的巨噬细胞HIV感染增加的机制
- 批准号:
9333313 - 财政年份:2015
- 资助金额:
$ 23.48万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
8040993 - 财政年份:2010
- 资助金额:
$ 23.48万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
9185430 - 财政年份:2010
- 资助金额:
$ 23.48万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
8637953 - 财政年份:2010
- 资助金额:
$ 23.48万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
8242055 - 财政年份:2010
- 资助金额:
$ 23.48万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
8446427 - 财政年份:2010
- 资助金额:
$ 23.48万 - 项目类别:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
多巴胺通过激活巨噬细胞多巴胺能系统加剧神经艾滋病
- 批准号:
7929994 - 财政年份:2010
- 资助金额:
$ 23.48万 - 项目类别:
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