Selenoproteins in Arsenic-Induced Metabolic Dysfunction

砷引起的代谢功能障碍中的硒蛋白

基本信息

  • 批准号:
    10328235
  • 负责人:
  • 金额:
    $ 49.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-02-01 至 2024-01-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Projected to afflict 642 million individuals globally by 2040, diabetes is a devastating metabolic disease that is increasingly tied to environmental toxicants. One such pollutant of immense public health significance is arsenic, which contaminates the drinking water for over 100 million individuals globally, including many living in the United States. Epidemiological evidence links arsenic exposure with diabetes; however, the mechanisms by which arsenic increases diabetes risk and the factors that modulate this risk remain incompletely known. Interestingly, arsenic and the essential element selenium have been known to have opposing biological functions for nearly 80 years. Selenium is incorporated into 25 unique proteins, selenoproteins, involved in cellular processes such as immune function, cell division, thyroid hormone metabolism, and redox handling. Built upon strengthening evidence that insulin-secreting pancreatic β-cells are a primary target of arsenic's metabolic toxicity and our preliminary studies demonstrating that selenoprotein deficiency augments arsenic's adverse effects on glucose metabolism, we propose the following central hypothesis: selenoproteins play an essential role in preserving glucose homeostasis by protecting insulin-secreting pancreatic β-cells from arsenic-induced dysfunction. To address this hypothesis, in Specific Aim 1 we will employ a novel β- cell-specific knockout of selenoproteins to examine the impact of this tissue-specific alteration on whole-body energy physiology as well as pancreatic islet architecture. To understand how reducing exposure to arsenic impacts diabetes risk, in Specific Aim 2 we will interrogate the conjecture that selenoproteins are required for recovery from arsenic-induced impairments in glucose metabolism; moreover, we will employ synchrotron X- ray fluorescence microscopy to perform tissue-level mapping of arsenic and selenium in pancreatic tissue to test the hypothesis that selenoproteins promote metabolic recovery by protecting pancreatic islets from arsenic accumulation and facilitating its clearance. In Specific Aim 3 we will expand upon our in vivo and cell line data to define the cellular defects in β-cell physiology induced by arsenic that are exacerbated by selenoprotein deficiency. In particular, we will focus on aspects of cellular physiology for which evidence suggests arsenic and selenium/selenoproteins have opposing actions, namely oxidative stress, AMP-activated protein kinase activity, and ATP generation. Furthermore, this aim will narrow in on a specific selenoprotein implicated in diabetes risk, glutathione peroxidase 1 (GPx1), to determine how this enzyme impacts arsenic-induced β-cell dysfunction and to ascertain whether common allelic variations in GPx1 account for differential sensitivity to arsenic-induced diabetes risk in humans. Collectively, the proposed studies will provide new knowledge regarding the essential role of selenoproteins in resisting arsenic-induced disruptions in glucose homeostasis, including identification of populations at heightened risk due to coexisting selenium deficiency and endemic arsenic exposure as well as those with polymorphisms in selenoproteins that enhance arsenic sensitivity.
项目总结/文摘

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Inappropriately sweet: Environmental endocrine-disrupting chemicals and the diabetes pandemic.
Underutilized and Under Threat: Environmental Policy as a Tool to Address Diabetes Risk.
  • DOI:
    10.1007/s11892-018-0993-5
  • 发表时间:
    2018-03-26
  • 期刊:
  • 影响因子:
    4.2
  • 作者:
    Shaikh S;Jagai JS;Ashley C;Zhou S;Sargis RM
  • 通讯作者:
    Sargis RM
Diabetes control is associated with environmental quality in the USA.
  • DOI:
    10.1530/ec-21-0132
  • 发表时间:
    2021-08-25
  • 期刊:
  • 影响因子:
    2.9
  • 作者:
    Jagai JS;Krajewski AK;Price KN;Lobdell DT;Sargis RM
  • 通讯作者:
    Sargis RM
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Robert M Sargis其他文献

Robert M Sargis的其他文献

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{{ truncateString('Robert M Sargis', 18)}}的其他基金

Protection against Arsenic-Induced Neurologic Defects by Brain DHA Enrichment
通过富含大脑 DHA 预防砷诱发的神经系统缺陷
  • 批准号:
    9806012
  • 财政年份:
    2019
  • 资助金额:
    $ 49.94万
  • 项目类别:
Protection against Arsenic-Induced Neurologic Defects by Brain DHA Enrichment
通过富含大脑 DHA 预防砷诱发的神经系统缺陷
  • 批准号:
    10018911
  • 财政年份:
    2019
  • 资助金额:
    $ 49.94万
  • 项目类别:
Selenoproteins in Arsenic-Induced Metabolic Dysfunction
砷引起的代谢功能障碍中的硒蛋白
  • 批准号:
    10091436
  • 财政年份:
    2018
  • 资助金额:
    $ 49.94万
  • 项目类别:
Metabolic Impact of Fetal or Adult Exposure to Environmental Endocrine Disruptors
胎儿或成人暴露于环境内分泌干扰物的代谢影响
  • 批准号:
    8723826
  • 财政年份:
    2013
  • 资助金额:
    $ 49.94万
  • 项目类别:
Metabolic Impact of Fetal or Adult Exposure to Environmental Endocrine Disruptors
胎儿或成人暴露于环境内分泌干扰物的代谢影响
  • 批准号:
    8582434
  • 财政年份:
    2013
  • 资助金额:
    $ 49.94万
  • 项目类别:
Environmental Endocrine Disruption of Adipocyte Metabolism
环境内分泌对脂肪细胞代谢的干扰
  • 批准号:
    8265337
  • 财政年份:
    2010
  • 资助金额:
    $ 49.94万
  • 项目类别:
Environmental Endocrine Disruption of Adipocyte Metabolism
环境内分泌对脂肪细胞代谢的干扰
  • 批准号:
    7953162
  • 财政年份:
    2010
  • 资助金额:
    $ 49.94万
  • 项目类别:
Environmental Endocrine Disruption of Adipocyte Metabolism
环境内分泌对脂肪细胞代谢的干扰
  • 批准号:
    8462609
  • 财政年份:
    2010
  • 资助金额:
    $ 49.94万
  • 项目类别:
Environmental Endocrine Disruption of Adipocyte Metabolism
环境内分泌对脂肪细胞代谢的干扰
  • 批准号:
    8144891
  • 财政年份:
    2010
  • 资助金额:
    $ 49.94万
  • 项目类别:
Environmental Endocrine Disruption of Adipocyte Metabolism
环境内分泌对脂肪细胞代谢的干扰
  • 批准号:
    8660690
  • 财政年份:
    2010
  • 资助金额:
    $ 49.94万
  • 项目类别:

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