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: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9729273
• 关键词: Vinyl; chloride; NAFLD; interaction

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.

肥胖及其代谢并发症在美国非常普遍，是主要的健康问题 和世界各地。事实上，肥胖可能会影响个体对其他环境暴露的敏感性， 氯乙烯（VC）。具体来说，我们假设实验性NAFLD和某些类型的消费 膳食脂肪如多不饱和脂肪酸（PUFA）使肝脏对VC敏感，作为第二次打击。因此我们 提出LA代谢物通过分子、细胞器和细胞使肝脏对VC肝毒性敏感 VC效应（NAFLD机制）。目标1.评价OXLAM在VC增强的肝细胞死亡中的作用 在NAFLD的动物模型中。具体而言，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饮食共同暴露的影响，B）确定 通过12/15-LO基因缺陷消除OXLAMs是否能减弱VC诱导的肝脏炎症， 损伤及相关机制。这项工作将在体内进行，比较野生型（WT）与12/15-LO 用靶向12/15-LO β或遗传（例如， 来源于12/15-LO KO小鼠的原代细胞）。基于初步数据的机制终点将包括 线粒体功能障碍、肝细胞死亡（坏死vs.凋亡）、ER应激和代谢/生物能量学 影响脂肪变性/细胞存活。这个R 03的目标建立在我的K 01研究的基础上，并扩展了该项目。 然而，在这里，我们正在建立在这个基础上，利用新的问题来调查一个特定的 脂肪类型（及其氧化代谢产物），在美国普遍存在。这一点与我的K 01截然不同，独一无二 研究，但将补充它非常恰当。这一提议符合NIDDK调查 肥胖的原因/后果。