Superfund Chemicals, Nutrition, and Multi-Organ Cardiovascular Risk

超级基金化学品、营养和多器官心血管风险

基本信息

  • 批准号:
    10596286
  • 负责人:
  • 金额:
    $ 19.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1997
  • 资助国家:
    美国
  • 起止时间:
    1997-04-07 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY The overall goal of Project 1 is to understand the signaling pathways and metabolic or biological changes by which bioactive nutrients modulate impacts of acute or chronic exposure to persistent organic pollutants such as polychlorinated biphenyls (PCBs) and long-chain per- and polyfluoroalkyl substances (PFAS). Such persistent pollutants express significant chemical stability in the environment, and toxic insults from POPs are known to correlate with a range of post-exposure human health impacts, including vascular inflammation. Atherosclerosis, a chronic inflammatory disease, remains the leading cause of death in the United States. Biological events associated with inflammation and atherosclerosis can be modified by circulating toxicants and bioactive nutrients and their metabolites, which dictate final redox changes and inflammatory outcomes, by altering NF-kB and Nrf2 signaling. For example, preliminary data demonstrate down-regulation of PCB 126- mediated toxicity and inflammation by plant-derived bioactive nutrients, e.g., polyphenols, and fiber (e.g., inulin). Importantly, it is known that the pathology of atherosclerosis is dependent on the health and cross-talk of multiple tertiary organ systems including the liver and gut, as exemplified by recent findings linking PCB exposure with increased plasma levels of trimethylamine N-oxide (TMAO), a diet-derived metabolite formed through cross-talk between gut microbiota and hepatic oxidation and associated with risk of atherosclerosis. Preliminary findings indicate that persistent organic pollutants, and especially PCBs, caused liver dysfunction and alterations of gut microbiota, and that prior liver injury exacerbated PCB-mediated systemic inflammation. Metabolomic profiling further suggested that increased formation of pro-atherogenic metabolites (e.g., ceramides) may drive multi-organ inflammation and increased cardiovascular risk. Based on these findings, three specific aims test the hypotheses that 1) administration of PCB 126 and/or PFAS to mice increases cardiometabolic disease risk by increasing ceramide production via modulation of hepatic gene expression and/or the gut microbiota; 2) administration of green tea catechins and/or soluble inulin fiber in vivo decreases ceramides and thereby stabilizes cellular redox status, modulating NF-kB and Nrf2 signaling and pro- atherosclerotic pathologies as determined by en face and lipid staining in atherogenic LDL receptor-deficient mice; and 3) exposure to PCBs and/or PFAS increases pro-atherogenic metabolites (e.g., ceramides) through increased de novo synthesis in preclinical models. Transcriptomic and metabolomic technologies will be used to explore the mechanistic interactions between pollutant exposure, nutritional intervention, and cardiovascular disease (CVD) risks. These data will be confirmed in biobanked samples of humans with CVD. Results will support the paradigm that healthful nutrition interventions offer a powerful strategy to reduce disease risks associated with environmental toxic insults and to prevent inflammatory diseases, such as atherosclerosis, that have been linked to exposure to Superfund pollutants.
项目总结

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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YEKATERINA ZAYTSEVA其他文献

YEKATERINA ZAYTSEVA的其他文献

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{{ truncateString('YEKATERINA ZAYTSEVA', 18)}}的其他基金

Fatty acid synthase in regulation of UDP-GlcNAc synthesis in colorectal cancer
脂肪酸合酶在结直肠癌中调节 UDP-GlcNAc 合成
  • 批准号:
    10287757
  • 财政年份:
    2021
  • 资助金额:
    $ 19.98万
  • 项目类别:
Fatty acid synthase in regulation of UDP-GlcNAc synthesis in colorectal cancer
脂肪酸合酶在结直肠癌中调节 UDP-GlcNAc 合成
  • 批准号:
    10437880
  • 财政年份:
    2021
  • 资助金额:
    $ 19.98万
  • 项目类别:
Targeting Lipid Metabolism in Colorectal Cancer
靶向结直肠癌的脂质代谢
  • 批准号:
    10117692
  • 财政年份:
    2021
  • 资助金额:
    $ 19.98万
  • 项目类别:
Targeting Lipid Metabolism in Colorectal Cancer
靶向结直肠癌的脂质代谢
  • 批准号:
    10594448
  • 财政年份:
    2021
  • 资助金额:
    $ 19.98万
  • 项目类别:
Targeting Lipid Metabolism in Colorectal Cancer
靶向结直肠癌的脂质代谢
  • 批准号:
    10374051
  • 财政年份:
    2021
  • 资助金额:
    $ 19.98万
  • 项目类别:

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