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Vinyl chloride-NAFLD interaction

Vinyl chloride-NAFLD interaction
氯乙烯-NAFLD 相互作用
批准号:
9729273
负责人:
Juliane I Beier
金额:
$4.37万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-01 至 2018-12-31

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中文摘要
翻译
肥胖及其代谢并发症非常普遍,是美国的主要健康问题 以及全世界。事实上,肥胖可能会影响个体对其他环境暴露的敏感性,例如 氯乙烯(VC)。具体来说,我们假设实验性 NAFLD 和某些类型的消费 膳食脂肪(例如多不饱和脂肪酸 (PUFA))会使肝脏对 VC 敏感,作为第二次打击。我们因此 提出 LA 代谢物通过分子、细胞器和细胞使肝脏对 VC 的肝毒性敏感 VC 效应(NAFLD 机制)。目标 1. 评估 OXLAM 在 VC 增强肝细胞死亡中的作用 在 NAFLD 动物模型中。具体来说,我们将: a) 确定 NAFLD/NAFLD 的剂量反应 亚急性 VC 暴露后的机制以及与 HF/LA 饮食同时暴露的影响,b) 确定 通过 12/15-LO 遗传缺陷消除 OXLAM 是否会减轻 VC 诱导的肝脏炎症和 损伤及其相关机制。这项工作将在体内进行,比较野生型 (WT) 与 12/15-LO 具有互补的体外模型的敲除小鼠,这些模型在药理学或遗传上以 12/15-LO 为目标(例如, 来自12/15-LO KO小鼠的原代细胞)。基于初步数据的机械终点将包括 线粒体功能障碍、肝细胞死亡(坏死与凋亡)、内质网应激和代谢/生物能学 影响脂肪变性/细胞存活。 R03 的目标建立在我的 K01 研究的基础上并扩展了该项目。 然而,在这里,我们在此基础上利用新问题来调查特定的角色 在美国流行的脂肪类型(及其氧化代谢物)。这个焦点与我的 K01 截然不同且独特 研究,但会非常恰当地补充它。该提案与 NIDDK 调查该问题的目标是一致的。 肥胖的原因/后果。
英文摘要
Obesity and its metabolic complications are highly prevalent and are major health problems in the United States and worldwide. Indeed, obesity may influence individual susceptibility to other environmental exposures such as vinyl chloride (VC). Specifically, we hypothesize that experimental NAFLD and the consumption of certain types of dietary fat such as poly-unsaturated fatty acids (PUFA) sensitize the liver to VC as a 2nd hit. We therefore propose that that LA metabolites sensitize the liver to VC hepatotoxicity via molecular, organelle, and cellular VC effects (NAFLD mechanisms). Aim 1. Evaluate the role of OXLAMs in VC-enhanced hepatocyte death in an animal model of NAFLD. Specifically, we will: a) determine the dose response for NAFLD/NAFLD mechanisms following sub-acute VC exposures and the impact of co-exposures with HF/LA diets, b) determine whether the ablation of OXLAMs via 12/15-LO genetic deficiency attenuates VC-induced liver inflammation and injury and the mechanisms involved. This work will be performed in vivo comparing wild-type (WT) to 12/15-LO knockout mice with complementary in vitro models that target 12/15-LO pharmacologically or genetically (e.g., primary cells derived from 12/15-LO KO mice). Mechanistic endpoints based on preliminary data will include mitochondrial dysfunction, hepatocyte death (necrosis vs. apoptosis), ER stress and metabolism/ bioenergetics impacting steatosis/cell survival. The aims of this R03 build on my K01 research and extend that project. However, here we are building on that foundation to leverage new questions in investigating the role of a specific fat type (and its oxidized metabolites) that is prevalent in the US. This focus is distinct and unique from my K01 research, but will complement it very aptly. This proposal is consistent with the goals of NIDDK to investigate the causes/consequences of obesity.
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会议论文
Vinyl chloride modifies the risk for nonalcoholic fatty liver disease
Vinyl chloride modifies the risk for nonalcoholic fatty liver disease
Enhancement of NAFLD risk by vinyl chloride: interaction of gut-liver-adipose axi
  • 批准号:
    8816090
  • 项目类别:
  • 资助金额:
    $12.07万
  • 财政年份:
    2013
  • 负责人:
    Juliane I Beier
  • 依托单位:
Enhancement of NAFLD risk by vinyl chloride: interaction of gut-liver-adipose axi
  • 批准号:
    8641352
  • 项目类别:
  • 资助金额:
    $12.07万
  • 财政年份:
    2013
  • 负责人:
    Juliane I Beier
  • 依托单位:
海外基金