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

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,会导致多种 严重的健康状况,吸毒者的健康结果比不吸毒者更差, 人口统计相似的人口。在中枢神经系统中,兴奋剂的使用会导致 通过更多地释放炎症因子和招募额外的神经炎症 白细胞。这使吸毒者更容易患上神经精神疾病、 脑血管和运动障碍,还可能加剧神经病理性影响 HIV、HCV 和多种细菌病原体感染。其精确途径 兴奋剂介导这些作用尚不清楚,但其中许多作用可能是由 药物相关的特定炎症触发因素(如 NF-kB)的激活。不过,直接链接 兴奋剂和这些神经炎症机制之间的关系尚未被描述。这 该提案的前提是多巴胺充当一种共同机制 兴奋剂激活骨髓细胞 NF-kB,从而引发或加剧 神经炎症。使用所有兴奋剂都会急剧增加中枢神经系统多巴胺水平,使细胞暴露 在富含多巴胺的大脑区域中,多巴胺浓度异常高。这些细胞中 细胞群是骨髓细胞,例如血管周围巨噬细胞和小胶质细胞,它们是 中枢神经系统中的初级免疫细胞。我们发表的研究表明,急性暴露于高浓度 多巴胺增加骨髓炎症细胞因子的产生,例如 IL-1b、IL-6、CXCL8 和CXCL10。我们的初步数据表明多巴胺通过激活 NF-kB 通路发挥作用 并启动 NLRP3 炎症小体,这是一种调节 IL-1b 释放的复合物,IL-1b 是一种主要的 炎症调节剂。介导这种作用的具体途径尚不清楚,因此 这些研究将产生有关特定多巴胺受体、基因和 介导多巴胺激活的蛋白质靶标 核因子kB 和人类巨噬细胞中的 NLRP3。 确定多巴胺诱导的具体信号传导机制和基因 NF-kB 活性的增加将表明可以针对改善 兴奋剂使用的神经炎症作用,显着改善长期健康结果 的兴奋剂用户。本提案中开发的数据将作为未来项目的基础 检查骨髓多巴胺能系统的调节作为治疗策略 限制与药物相关的神经系统疾病和炎症发生率的增加 虐待。这些项目将研究新型效应器和现有效应器的重新利用 多巴胺能疗法可减轻兴奋剂滥用人群的炎症。

项目成果

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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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