Involvement of microglial α7AChR in binge alcohol modulation of gut dysbiosis

小胶质细胞α7AChR参与酗酒调节肠道菌群失调

基本信息

  • 批准号:
    10527744
  • 负责人:
  • 金额:
    $ 22.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-16 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Binge alcohol drinking is very common among the young people. Excessive alcohol consumption affects innate immune signaling in the gut and the brain by altering gene expression and molecular pathways which lead to alcohol use disorder (AUD). The binge alcohol-modulated gut-brain axis, retrogradely, is associated with neuroinflammation and microglial activation. On the other hand, binge alcohol, anterogradely, may cause neuroinflammation-mediated gut dysbiosis, via the “microglia-gut axis”. Targeting the neuroimmune system is a new avenue for developing and repurposing effective pharmacotherapies and it is clinically relevant and highly significant. The nicotinic alpha7 acetylcholine receptor (7AChR), which is expressed in microglia regulates neuroinflammation through cholinergic anti-inflammatory pathway. Our published data and other study showed that lipopolysaccharide (LPS)-induced inflammation releases pro-inflammatory cytokines and upregulates non- functional 7AChR (futile) in macrophages and microglia. Stimulation of futile 7AChR with GTS-21 (7AChR agonist), decreases LPS-induced TNF release in macrophages, and knockdown of 7AChR with 7AChR siRNA in LPS-induced macrophages abolish GTS-21 beneficial effects. Our preliminary studies demonstrated that mice given binge ethanol (EtOH) suffer with gut dysbiosis and continuously exhibit significant differences in -diversity along with an increase in commensal proportions of Prevotellaceae family. Taken these premises together, we hypothesize that binge EtOH exposure causes neuroinflammation and gut dysbiosis due to the release of proinflammatory cytokines, which lead to microglial activation and increased expression of microglial 7AChR (futile), and bioinformatic analysis of these factors could establish a functional relationship among them. In in vivo, disruption of microglia and microglial 7AChR utilizing PLX-5622 (microglia depletion reagent) and microglial 7AChR conditional knockout (7AChRcKO) mice, respectively, will elucidate the discrete roles of microglia and microglial 7AChR after binge EtOH exposure. The pharmacological intervention of GTS-21 in vivo will reverse EtOH-induced effects on microglia activation, neuroinflammation and gut dysbiosis involving 7AChR. To test these hypotheses, we have posited two specific aims. Aim 1 is to characterize activation of microglia, neuroinflammation and gut dysbiosis following binge EtOH exposure using C57BL/6J (B6) mice and bioinformatics tools. Aim 2 is to elucidate the involvement of microglial 7AChR and role of microglia in alcohol- modulation of neuroinflammation and gut dysbiosis by utilizing B6 and 7AChRcKO mice using PLX-5622 and GTS-21. Our innovative project with high clinical relevance, might have high risk, yet very likely high reward. Successful completion of this R21 project shall shift the paradigm from observing the gut-brain axis to understanding and pharmacologically targeting the microglia-gut axis following binge exposure to EtOH and would allow us to develop a full length R01 project to target the neuroimmune signaling in developing and repurposing effective pharmacotherapies for alcohol drinkers.
酗酒在年轻人中很常见。过度饮酒影响先天 肠道和大脑中的免疫信号通过改变基因表达和分子途径而导致 酒精使用障碍(AUD)。过度饮酒调制的肠脑轴,退行性地与 神经炎症和小胶质细胞活化。另一方面,酗酒,顺势而为,可能会导致 神经炎症通过“小胶质细胞-肠轴”介导的肠道生物失调。瞄准神经免疫系统是一种 开发和再利用有效的药物治疗的新途径,具有临床相关性和高度的 意义重大。表达于小胶质细胞的烟碱型α7乙酰胆碱受体(7AChR)调节 通过胆碱能抗炎途径引起神经炎症。我们公布的数据和其他研究表明 脂多糖(LPS)诱导的炎症释放促炎细胞因子并上调非 巨噬细胞和小胶质细胞的功能性7AChR(无效)。GTS-21(7AChR)对无效的7AChR的刺激作用 激动剂),减少内毒素诱导的巨噬细胞肿瘤坏死因子的释放,并用7AChR敲除7AChR 脂多糖诱导的巨噬细胞中的siRNA可消除GTS-21的有益作用。我们的初步研究表明 给予过量乙醇(Etoh)的小鼠出现肠道生物失调,并持续表现出显著的差异 多样性与普氏豆科植物共生比例的增加。拿走了这些房舍 总之,我们假设过量接触乙醇会导致神经炎症和肠道生物失调,这是由于 释放促炎细胞因子,导致小胶质细胞活化和表达增加 7AChR(无用),对这些因子进行生物信息学分析可以建立它们之间的功能关系。 在体内,小胶质细胞和小胶质细胞7AChR被PLX-5622(小胶质细胞耗竭试剂)和 小胶质细胞7AChR条件性基因敲除(7AChRcKO)小鼠,将阐明不同的作用 暴饮乙醇后小胶质细胞和小胶质细胞7AChR。GTS-21的药理干预作用 Vivo将逆转乙醇诱导的小胶质细胞激活、神经炎症和肠道生物失调的作用,涉及 7AChR.为了检验这些假设,我们设定了两个具体目标。目标1是表征激活的 暴饮乙醇暴露后的小胶质细胞、神经炎症和肠道生物失调 生物信息学工具。目的2阐明小胶质细胞7AChR的参与及其在酒精中毒中的作用。 利用B6和7AChRcKO小鼠对神经炎症和肠道生物失调的调节 GTS-21。我们的创新项目具有很高的临床相关性,可能有很高的风险,但很可能有很高的回报。 这个R21项目的成功完成将把范式从观察肠道-脑轴转移到 暴饮暴食乙醇和乙醇后小胶质细胞-肠系轴的理解和药理学靶向 将使我们能够开发一个全长的R01项目来针对神经免疫信号在开发和 为饮酒者重新设计有效的药物疗法。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

SULIE L. CHANG其他文献

SULIE L. CHANG的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('SULIE L. CHANG', 18)}}的其他基金

Effects of binge ethanol on neuroinflammation and neurodegeneration with high fat diets
暴饮乙醇对高脂肪饮食引起的神经炎症和神经变性的影响
  • 批准号:
    10668068
  • 财政年份:
    2023
  • 资助金额:
    $ 22.01万
  • 项目类别:
Involvement of microglial α7AChR in binge alcohol modulation of gut dysbiosis
小胶质细胞α7AChR参与酗酒调节肠道菌群失调
  • 批准号:
    10705750
  • 财政年份:
    2022
  • 资助金额:
    $ 22.01万
  • 项目类别:
Modulation of OPRM1 alternative splicing by morphine and HIV-1 Nef
吗啡和 HIV-1 Nef 对 OPRM1 选择性剪接的调节
  • 批准号:
    10654016
  • 财政年份:
    2021
  • 资助金额:
    $ 22.01万
  • 项目类别:
Methylation in binge ethanol-induced spleen atrophy in adolescent rats
青春期大鼠暴食乙醇引起的脾萎缩的甲基化
  • 批准号:
    10400702
  • 财政年份:
    2018
  • 资助金额:
    $ 22.01万
  • 项目类别:
Immunomodulation of nicotine in HIV-1Tg rat brain
尼古丁对 HIV-1Tg 大鼠脑的免疫调节作用
  • 批准号:
    10378566
  • 财政年份:
    2018
  • 资助金额:
    $ 22.01万
  • 项目类别:
Immunomodulation of nicotine in HIV-1Tg rat brain
尼古丁对 HIV-1Tg 大鼠脑的免疫调节作用
  • 批准号:
    9897503
  • 财政年份:
    2018
  • 资助金额:
    $ 22.01万
  • 项目类别:
Methylation in binge ethanol-induced spleen atrophy in adolescent rats
青春期大鼠暴食乙醇引起的脾萎缩的甲基化
  • 批准号:
    10155374
  • 财政年份:
    2018
  • 资助金额:
    $ 22.01万
  • 项目类别:
Alcohol-induced Impairment of Endothelial Cell Recovery
酒精引起的内皮细胞恢复损伤
  • 批准号:
    9238541
  • 财政年份:
    2017
  • 资助金额:
    $ 22.01万
  • 项目类别:
Involvement of TRP Channels in Ethanol Concentration-Dependent Effects on Immune
TRP 通道参与乙醇浓度依赖性免疫效应
  • 批准号:
    8740695
  • 财政年份:
    2014
  • 资助金额:
    $ 22.01万
  • 项目类别:
Involvement of TRP Channels in Ethanol Concentration-Dependent Effects on Immune
TRP 通道参与乙醇浓度依赖性免疫效应
  • 批准号:
    8936414
  • 财政年份:
    2014
  • 资助金额:
    $ 22.01万
  • 项目类别:

相似海外基金

REU Site: Design, Create, and Innovate 3-Dimensional User Interfaces to Improve Human Sensory and Motor Performance in Virtual Environments (HUMANS MOVE)
REU 网站:设计、创建和创新 3 维用户界面,以提高虚拟环境中的人类感官和运动表现 (HUMANS MOVE)
  • 批准号:
    2349771
  • 财政年份:
    2024
  • 资助金额:
    $ 22.01万
  • 项目类别:
    Standard Grant
CAREER: Atomic-level understanding of stability and transition kinetics of 3-dimensional interfaces under irradiation
职业:对辐照下 3 维界面的稳定性和转变动力学的原子水平理解
  • 批准号:
    2340085
  • 财政年份:
    2024
  • 资助金额:
    $ 22.01万
  • 项目类别:
    Continuing Grant
Artificial fabrication of 3-dimensional noncollinear magnetic order and magnetization manipulation by spin torque
三维非共线磁序的人工制造和自旋转矩磁化操纵
  • 批准号:
    23H00232
  • 财政年份:
    2023
  • 资助金额:
    $ 22.01万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Understanding of 3-dimensional seismic behavior of RC frame high-speed railway/highway viaducts using FE analysis
使用有限元分析了解 RC 框架高速铁路/公路高架桥的 3 维抗震性能
  • 批准号:
    23H01489
  • 财政年份:
    2023
  • 资助金额:
    $ 22.01万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Modernization of 3-dimensional printing capabilities at the Aquatic Germplasm and Genetic Resource Center
水产种质和遗传资源中心 3 维打印能力的现代化
  • 批准号:
    10736961
  • 财政年份:
    2023
  • 资助金额:
    $ 22.01万
  • 项目类别:
The 3-dimensional nest of the honey bee: organization, development, and impact on colony function
蜜蜂的 3 维巢穴:组织、发育及其对蜂群功能的影响
  • 批准号:
    2216835
  • 财政年份:
    2023
  • 资助金额:
    $ 22.01万
  • 项目类别:
    Standard Grant
Research on high-density 3-dimensional polymer optical waveguide device for photonics-electronics convergence
光电子融合高密度三维聚合物光波导器件研究
  • 批准号:
    23H01882
  • 财政年份:
    2023
  • 资助金额:
    $ 22.01万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Scaff-Net: 3 Dimensional multiphoton polymerisation printed scaffolds for medium throughput recording from stem cell derived human cortical networks.
Scaff-Net:3 维多光子聚合打印支架,用于从干细胞衍生的人类皮质网络进行中等通量记录。
  • 批准号:
    EP/X018385/1
  • 财政年份:
    2023
  • 资助金额:
    $ 22.01万
  • 项目类别:
    Research Grant
3-dimensional prompt gamma imaging for online proton beam dose verification
用于在线质子束剂量验证的 3 维瞬发伽马成像
  • 批准号:
    10635210
  • 财政年份:
    2023
  • 资助金额:
    $ 22.01万
  • 项目类别:
Equipment: MRI: Track 1 Acquisition of a 3-Dimensional Nanolithography Instrument
设备:MRI:轨道 1 获取 3 维纳米光刻仪器
  • 批准号:
    2320636
  • 财政年份:
    2023
  • 资助金额:
    $ 22.01万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了