Perfluoroalkanoate (PFAS) modulation of the inflammatory response through potent inhibition of arachidonic acid metabolizing cyclooxygenase and cytochrome P450 enzymes

全氟链烷酸酯 (PFAS) 通过有效抑制花生四烯酸代谢环加氧酶和细胞色素 P450 酶来调节炎症反应

基本信息

  • 批准号:
    10532243
  • 负责人:
  • 金额:
    $ 22.72万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-12-01 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY The ubiquitous environmental contaminants collectively known as PFAS (Per- and polyfluoroalkyl substances) have been dubbed “forever chemicals” due to their persistence in the environment. In humans, they have been associated with a wide variety of illnesses, including: cancer, immunotoxicities, hepatotoxicity hyperlipidemias, and developmental defects. Despite their toxicological threat to human health, the exact molecular mechanisms by which they exert their effects have remained elusive. A common theme existing between many of these disease states is the disruption of immune system homeostasis, which manifests itself in an increased risk for cancer and other immunotoxicities. Our long-term goal is to delineate the molecular mechanisms related to PFAS-induced innate immune system dysfunction in the liver. The objective of this particular application is to characterize how PFAS, through modulation of key metabolic enzymes, may impact the production of oxylipins by hepatocytes. The impact of these findings will provide mechanistic insight into which innate immune cell mediators contribute to immunosuppression by PFAS. Our central hypothesis is that CYP, COX, and LOX inhibition by PFAS leads to dysregulation of oxylipin synthesis, promoting immune suppression. We will test this hypothesis through employing two specific aims. In our first aim, we will identify the CYP, COX, and LOX oxylipin metabolic pathways inhibited by the PFAS compounds via direct enzyme inhibition assays and a targeted lipidomics approach. This aim will define the impacts of PFAS on the generation of liver-derived inflammatory mediators in exposed individuals. In our second aim, we will characterize the inflammatory response to LPS in PFAS-exposed primary hepatocytes. Here, we will characterize oxylipin metabolism and cytokine production in response to PFAS and LPS exposure to delineate how hepatocytes respond to inflammatory signals after PFAS exposure, thus providing insight into the potential health effects during an immunological challenge. To date, the potential effects of PFAS on hepatic immune responses is not well understood. This proposal will further delineate the molecular mechanisms of PFAS on oxylipin production and immunological challenge, providing a strong foundation for understanding the role of PFAS in immune system dysregulation, which is key to developing treatments for those who have been exposed and preventing the observed immunopathology.
项目总结

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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Jed Noah Lampe其他文献

Jed Noah Lampe的其他文献

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{{ truncateString('Jed Noah Lampe', 18)}}的其他基金

Perfluoroalkanoate (PFAS) modulation of the inflammatory response through potent inhibition of arachidonic acid metabolizing cyclooxygenase and cytochrome P450 enzymes
全氟链烷酸酯 (PFAS) 通过有效抑制花生四烯酸代谢环加氧酶和细胞色素 P450 酶来调节炎症反应
  • 批准号:
    10373848
  • 财政年份:
    2021
  • 资助金额:
    $ 22.72万
  • 项目类别:
The role of CYP3A7 in the disposition and toxicity of HIV inhibitors in the developing infant
CYP3A7 在 HIV 抑制剂在发育婴儿中的处置和毒性中的作用
  • 批准号:
    10408010
  • 财政年份:
    2018
  • 资助金额:
    $ 22.72万
  • 项目类别:
The role of CYP3A7 in the disposition and Toxicity of HIV inhibitors in the developing infant
CYP3A7 在 HIV 抑制剂对发育中婴儿的处置和毒性中的作用
  • 批准号:
    10012258
  • 财政年份:
    2018
  • 资助金额:
    $ 22.72万
  • 项目类别:
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