Arsenical production in germ free and humanized mice

无菌小鼠和人源化小鼠中砷的产生

基本信息

  • 批准号:
    9198224
  • 负责人:
  • 金额:
    $ 18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-01-01 至 2017-12-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Arsenic poisoning, or arsenicosis, is a worldwide threat to public health, leading to a variety of human diseases, including cancer. The microbial community (microbiome) of the human GI tract (GIT) has been implicated as a significant influence on host exposure to toxic xenobiotics, including arsenic-containing compounds (arsenicals), but the individual roles of host vs. microbiome in arsenic biotransformation have not been clearly defined. Our preliminary data in mice strongly suggest that the microbiome decreases arsenic toxicity in the host. The broad, long-term objective of this research is to bette understand the functional components of the human microbiome that impact As-transformations in the GIT that can then be manipulated as prophylactic and/or detoxifying agents for use as novel treatment and prevention strategies against human arsenicosis. This research addresses the microbiome's role in human exposure to an environmental toxin and so specifically addresses a strategic theme ("Exposure Research") and a specific strategic goal (Goal 4, part b) of the National Institute of Environmental Health Sciences (NIEHS). As an initial step toward defining the role of the human microbiome in arsenicosis, Specific Aim 1 will establish the baseline production of arsenicals in germ free mice and germ free mice colonized with a human microbiome (humanized mice). Germ free mice are completely sterile and so arsenical production in these arsenic-exposed animals will be due to host metabolism alone. In contrast, arsenical production in humanized mice will reflect the net influence of host and microbe, thereby allowing a comparison of their individual roles. As the next step forward in defining the role of the human microbiome in arsenicosis, Specific Aim 2 will directly quantify the influence of microbially- produced, arsenic-active enzymes in the gastrointestinal tract on arsenical levels in gnotobiotic mice. In this part of the project, germ free mice will be mono-associated with genetically defined strains of Escherichia coli that have been shown previously to metabolize arsenic in specific ways. Arsenical production will be quantified from temporally collected mouse tissues and excretia by state-of-the-art methodology using high-performance liquid chromatography and inductively coupled plasma mass spectrometry (HPLC-ICPMS) and corresponding temporal microbiome dynamics will be tracked using 16S rRNA encoding gene metagenomic sequencing. These data will be analyzed together to provide statistical support to and experimental evidence for the in vivo transformation of arsenic by the human GIT microbiome.
 描述(由申请人提供):砷中毒或砷中毒是一种全球性的公共健康威胁,导致多种人类疾病,包括癌症。人类胃肠道(GIT)的微生物群落(微生物组)对宿主暴露于有毒的外源性物质(包括含砷化合物)有显著影响,但宿主与微生物组在砷生物转化中的个体作用尚未明确定义。我们在小鼠中的初步数据强烈表明,微生物组降低了宿主中的砷毒性。这项研究的广泛,长期目标是更好地了解人类微生物组的功能成分,这些功能成分影响GIT中的As转化,然后可以作为预防和/或解毒剂,用于治疗和预防人类砷中毒的新策略。这项研究解决了微生物组在人类暴露于环境毒素中的作用,因此具体解决了国家环境健康科学研究所(NIEHS)的战略主题(“暴露研究”)和具体战略目标(目标4,B部分)。作为确定人类微生物组在砷中毒中作用的第一步,具体目标1将建立无菌小鼠和无菌小鼠(人源化小鼠)中砷的基线生产。无菌小鼠是完全无菌的,因此在这些砷暴露的动物中砷的产生将仅仅是由于宿主代谢。相比之下,人源化小鼠中砷的产生将反映宿主和微生物的净影响,从而允许比较它们各自的作用。作为确定人类微生物组在砷中毒中作用的下一步,具体目标2将直接量化 微生物产生的,砷活性酶在胃肠道的砷水平在gnotobiotic小鼠。在项目的这一部分,无菌小鼠将与先前已显示以特定方式代谢砷的大肠杆菌的遗传定义菌株单相关。将使用高效液相色谱法和电感耦合等离子体质谱法(HPLC-ICPMS)通过最先进的方法从暂时收集的小鼠组织和排泄物中定量砷的产生,并将使用16 S rRNA编码基因宏基因组测序跟踪相应的暂时微生物组动态。这些数据将一起进行分析,为人体GIT微生物组对砷的体内转化提供统计支持和实验证据。

项目成果

期刊论文数量(1)
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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Timothy McDermott其他文献

Timothy McDermott的其他文献

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{{ truncateString('Timothy McDermott', 18)}}的其他基金

Neurophysiological mechanisms of anhedonia and cognitive control deficits in trauma-exposed people completing vibroacoustically augmented breath focused mindfulness
创伤暴露人群完成振动声学增强呼吸聚焦正念的快感缺失和认知控制缺陷的神经生理机制
  • 批准号:
    10752342
  • 财政年份:
    2023
  • 资助金额:
    $ 18万
  • 项目类别:
Self-regulation of Prefrontal Cortex during Emotional Cognitive Control
情绪认知控制过程中前额叶皮层的自我调节
  • 批准号:
    10376765
  • 财政年份:
    2020
  • 资助金额:
    $ 18万
  • 项目类别:
Mechanisms of arsenic detoxification by the human microbiome
人体微生物组的砷解毒机制
  • 批准号:
    9750648
  • 财政年份:
    2017
  • 资助金额:
    $ 18万
  • 项目类别:
Mechanisms of arsenic detoxification by the human microbiome
人体微生物组的砷解毒机制
  • 批准号:
    9977978
  • 财政年份:
    2017
  • 资助金额:
    $ 18万
  • 项目类别:
Mechanisms of arsenic detoxification by the human microbiome
人体微生物组的砷解毒机制
  • 批准号:
    10207533
  • 财政年份:
    2017
  • 资助金额:
    $ 18万
  • 项目类别:
Mechanisms of arsenic detoxification by the human microbiome
人体微生物组的砷解毒机制
  • 批准号:
    9290254
  • 财政年份:
    2017
  • 资助金额:
    $ 18万
  • 项目类别:

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