Project 3: Gut microbiome -arsenic- diabetes interactions

项目 3:肠道微生物组-砷-糖尿病的相互作用

基本信息

  • 批准号:
    10570876
  • 负责人:
  • 金额:
    $ 31.56万
  • 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:
    2020-02-20 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT: PROJECT 3 Exposure to inorganic arsenic (iAs) affects large human populations worldwide and leads to a number of human diseases, including diabetes. Project 3 addresses a fundamental gap in understanding mechanisms underlying iAs-induced diabetes – specifically the role of the gut microbiome. The association between iAs and diabetes has been established in numerous epidemiological studies. We and others have also demonstrated that iAs induces dysregulation of glucose and insulin metabolism in mice. The gut microbiome has a profound effect on human health through its key role in metabolic regulation, and emerges as a promising target for intervention and therapeutic treatment in human health. Accumulating evidence supports the role of the gut microbiome and Farnesoid X receptor (FXR) in the pathogenies and prevention of diabetes in both animals and humans. Our studies are among the first to demonstrate the functional interactions between iAs and the gut microbiome. Still, precisely how the iAs-altered gut microbiome affects diabetes risk remains to be determined. In particular, the molecular mechanisms underlying iAs-microbiome-host crosstalk are largely unknown. This represents a significant gap in iAs-microbiome research, which also impedes mechanism-based interventions to reduce arsenic-induced diabetes via targeting the gut microbiome and its metabolic functions. Our central hypothesis is that modulation of the gut microbiome will serve as a method for reduction of iAs-perturbed metabolic dysfunction/diabetes. Specifically, iAs-altered gut microbiome disrupts bile acids to inhibit FXR, which in turn alters gluconeogenesis and insulin signaling. Our robust preliminary data underscore the key role of microbiome- bile acid-FXR axis in iAs-induced diabetes, and highlight the potential to modulate iAs toxicity by targeting FXR via microbiome. To test this hypothesis, we will pursue three specific aims: Aim 1: Establish the functional link between altered gut microbiota and iAs-impaired bile acid metabolism; Aim 2: Determine the effects of inhibited FXR activation, driven by iAs-induced gut microbiome dysbiosis, on gluconeogenesis and insulin signaling; and Aim 3: Mediate iAs-induced diabetes via restoring FXR activation by gut microbiome manipulation. Our strong team (Drs. Lu, Sartor, Styblo and McDermott) has complimentary expertise in iAs toxicity, gut microbiome, iAs metabolism and iAs-induced diabetes. We use innovative techniques to characterize largely unknown contributions of gut microbiome-bile acid-FXR in iAs-induced diabetes and the project is in line with the theme of the UNC-SRP “Identifying novel methods to reduce iAs exposure and elucidating mechanisms underlying iAs- induced metabolic dysfunction with a vision for disease prevention.” The highly modifiable nature of the gut microbiome and in-depth mechanistic understanding of the role of microbiome in disease will allow us to develop new tangible approaches to reduce iAs-induced diabetes by targeting the gut microbiome and related signaling molecules.
摘要:项目3 暴露于无机砷(iAs)会影响全世界的大量人群,并导致许多人类疾病。 疾病,包括糖尿病。项目3解决了在理解基本机制方面的一个根本差距 iAs诱导的糖尿病-特别是肠道微生物组的作用。iAs与糖尿病之间的关系 已经在许多流行病学研究中得到证实。我们和其他人还证明, 在小鼠中诱导葡萄糖和胰岛素代谢失调。肠道微生物组对 通过其在代谢调节中的关键作用,人类健康,并成为一个有希望的干预目标 和治疗性治疗。越来越多的证据支持肠道微生物组的作用, 法尼醇X受体(FXR)在动物和人类糖尿病的病因和预防中的作用。我们 这些研究是最早证明iAs和肠道微生物组之间的功能性相互作用的研究之一。不过, iAs改变的肠道微生物组如何确切地影响糖尿病风险仍有待确定。特别是 作为iAs-微生物组-宿主串扰基础的分子机制在很大程度上是未知的。这表示 iAs微生物组研究存在重大差距,这也阻碍了基于机制的干预措施, 砷诱导的糖尿病通过靶向肠道微生物组及其代谢功能。我们的核心假设 肠道微生物组调节将作为减少iAs干扰的代谢的方法 功能障碍/糖尿病。具体来说,iAs改变的肠道微生物组破坏胆汁酸以抑制FXR,这反过来又会影响FXR的表达。 改变胰岛素生成和胰岛素信号传导。我们强大的初步数据强调了微生物组的关键作用- iAs诱导的糖尿病中胆汁酸-FXR轴,并强调通过靶向FXR调节iAs毒性的潜力 通过微生物组为了检验这一假设,我们将追求三个具体目标:目标1:建立功能联系 肠道微生物群改变与胰岛素抵抗受损的胆汁酸代谢之间的关系;目的2:确定抑制胰岛素抵抗的影响。 由iAs诱导的肠道微生物组生态失调驱动的FXR激活,对胰岛素生成和胰岛素信号传导的影响;以及 目的3:通过肠道微生物组操纵恢复FXR激活来介导iAs诱导的糖尿病。我们强大 团队(Lu、Sartor、Styblo和McDermott博士)在iAs毒性、肠道微生物组、iAs 代谢和iAs诱导的糖尿病。我们使用创新的技术来描述大部分未知的 肠道微生物组-胆汁酸-FXR在iAs诱导的糖尿病中的贡献,该项目符合主题 UNC-SRP“确定减少iAs暴露的新方法并阐明iAs的潜在机制- 以预防疾病为愿景的代谢功能障碍。”肠道的高度可变性 微生物组和深入了解微生物组在疾病中的作用机制将使我们能够开发 通过靶向肠道微生物组和相关信号传导减少iAs诱导的糖尿病的新的切实方法 分子。

项目成果

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Kun Lu其他文献

Kun Lu的其他文献

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{{ truncateString('Kun Lu', 18)}}的其他基金

Acquisition of Inductively Coupled Plasma Mass Spectrometry for Elemental Analysis
获取用于元素分析的电感耦合等离子体质谱仪
  • 批准号:
    10415598
  • 财政年份:
    2022
  • 资助金额:
    $ 31.56万
  • 项目类别:
Core D: Chemistry and Analytical Core (CAC)
核心 D:化学和分析核心 (CAC)
  • 批准号:
    10570856
  • 财政年份:
    2020
  • 资助金额:
    $ 31.56万
  • 项目类别:
The gut microbiome and glyphosate neurotoxicity
肠道微生物组和草甘膦的神经毒性
  • 批准号:
    10229481
  • 财政年份:
    2020
  • 资助金额:
    $ 31.56万
  • 项目类别:
The gut microbiome and glyphosate neurotoxicity
肠道微生物组和草甘膦的神经毒性
  • 批准号:
    10040711
  • 财政年份:
    2020
  • 资助金额:
    $ 31.56万
  • 项目类别:
Functional interaction between the gut microbiome and arsenic exposure
肠道微生物组与砷暴露之间的功能相互作用
  • 批准号:
    9008042
  • 财政年份:
    2015
  • 资助金额:
    $ 31.56万
  • 项目类别:
Functional interaction between the gut microbiome and arsenic exposure
肠道微生物组与砷暴露之间的功能相互作用
  • 批准号:
    8814331
  • 财政年份:
    2015
  • 资助金额:
    $ 31.56万
  • 项目类别:
Functional interaction between the gut microbiome and arsenic exposure
肠道微生物组与砷暴露之间的功能相互作用
  • 批准号:
    9187023
  • 财政年份:
    2015
  • 资助金额:
    $ 31.56万
  • 项目类别:
Biomarkers of formaldehyde based on DNA-protein cross-links
基于 DNA-蛋白质交联的甲醛生物标志物
  • 批准号:
    8747851
  • 财政年份:
    2014
  • 资助金额:
    $ 31.56万
  • 项目类别:
Biomarkers of formaldehyde based on DNA-protein cross-links
基于 DNA-蛋白质交联的甲醛生物标志物
  • 批准号:
    8850443
  • 财政年份:
    2014
  • 资助金额:
    $ 31.56万
  • 项目类别:
Molecular Analysis and Statistical Support Facility Core (MASS)
分子分析和统计支持设施核心 (MASS)
  • 批准号:
    10414005
  • 财政年份:
    2001
  • 资助金额:
    $ 31.56万
  • 项目类别:

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