Understanding the influence of n-3 PUFA on pro-inflammatory aspects of mercury

了解 n-3 PUFA 对汞促炎作用的影响

基本信息

批准号：
8516514
负责人：
ALLEN J ROSENSPIRE
金额：
$ 22.34万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516514
关键词：
Adverse effects Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Apoptosis Autoimmune Diseases Autoimmune Process Cell Death Cell membrane Cessation of life Chronic Complex Data Defect Depressed mood Diet Environmental Exposure Epidemiologic Studies Exposure to Faeroe Islands Failure Fatty Acids Fishes Heavy Metals Homeostasis Human Immune system Immunomodulators Impaired cognition In Vitro Individual Inflammation Inflammatory Ingestion Intoxication Lead Ligands Link Lymphatic Diseases Lymphocyte Mammals Maps Mediating Membrane Microdomains Mercury Molecular N-3 polyunsaturated fatty acid Neurotoxins New Zealand Oceans Paper Pathway interactions Polyunsaturated Fatty Acids Population Property Reporting Research Research Personnel Resistance Risk Sea Seafood Series Seychelles Signal Transduction Source Structure Syndrome T-Lymphocyte TNFRSF6 gene Techniques Technology Testing Time Toxic effect Western Blotting Work attenuation base cohort design immunopathology in vivo in vivo Model interest lupus-like lymphocyte proliferation neurodevelopment prevent

项目摘要

DESCRIPTION (provided by applicant): The environmental heavy metal contaminant mercury (Hg) is a potent neurotoxin and immunomodulator that at low exposure levels has been implicated as a factor contributing to cognitive impairment as well as to inflammation and autoimmune disease in animal models and in human populations. However epidemiological studies of low level Hg intoxicated populations who also consume large amounts of fish, seem to show that these populations are more resistant to the detrimental effects of Hg than are equally Hg intoxicated populations who do not consume such large quantities of fish. Since fish have particularly high levels of n-3 polyunsaturated fatty acids (n-3 PUFA), it has been suggested that detrimental effects of low-level Hg intoxication may be counteracted by dietary ingestion of n-3 PUFA. Presently there is no mechanistic understanding of how n-3 PUFA might interact with Hg so as to prevent the harmful effects of low-level intoxication. However we have previously shown that one consequence of low-level Hg intoxication is that Fas (CD95) mediated signal transduction and activation induced cell death (AICD) in the immune system is depressed. CD95 signaling and AICD are physiologically important in maintaining immune system homeostasis, and attenuation of CD95 signaling is well known to be associated with an autoimmune proliferative syndrome characterized by lymphadenopathy and a lupus-like inflammatory immunopathology in animals and humans. On the other hand, several investigators have reported that n-3 PUFA have anti- inflammatory properties, as diets rich in these fatty acids are effective in ameliorating several autoimmune diseases. Significantly, it has also been reported that the anti-inflammatory properties of n-3 PUFA may be linked to their ability to enhance CD95 signaling and AICD. These findings lead to the hypothesis that high dietary inputs of n-3 PUFA will prevent harmful effects of low-level Hg intoxication by restoring the ability of CD95 to properly signal AICD in activated, but Hg intoxicated lymphocytes. This proposal is designed to rigorously test this hypothesis. Both in vitro and in vivo models will be employed, where the plan is to utilize western blotting techniques, as well as flow cytometric-based technology to map CD95 signaling networks.

描述（由申请人提供）：环境重金属污染物汞 (Hg) 是一种强效神经毒素和免疫调节剂，在低暴露水平下，它被认为是导致动物模型和动物模型中认知障碍以及炎症和自身免疫性疾病的一个因素。人口。然而，对同时食用大量鱼类的低水平汞中毒人群的流行病学研究似乎表明，这些人群比不食用大量鱼类的同等汞中毒人群对汞的有害影响具有更强的抵抗力。由于鱼类的 n-3 多不饱和脂肪酸 (n-3 PUFA) 含量特别高，因此有人建议，通过饮食摄入 n-3 PUFA 可以抵消低水平汞中毒的有害影响。目前，对于 n-3 PUFA 如何与汞相互作用以防止低浓度中毒的有害影响，尚无机制了解。然而，我们之前已经表明，低水平汞中毒的后果之一是免疫系统中 Fas (CD95) 介导的信号转导和激活诱导细胞死亡 (AICD) 受到抑制。 CD95 信号传导和 AICD 在维持免疫系统稳态方面具有重要的生理意义，众所周知，CD95 信号传导的减弱与动物和人类中以淋巴结肿大和狼疮样炎症免疫病理学为特征的自身免疫增殖综合征相关。另一方面，一些研究人员报告说，n-3 PUFA 具有抗炎特性，因为富含这些脂肪酸的饮食可有效改善多种自身免疫性疾病。值得注意的是，据报道，n-3 PUFA 的抗炎特性可能与其增强 CD95 信号传导和 AICD 的能力有关。这些发现得出这样的假设：n-3 PUFA 的高膳食摄入量将通过恢复 CD95 在激活但汞中毒的淋巴细胞中正确向 AICD 发出信号的能力来防止低水平汞中毒的有害影响。该提案旨在严格检验这一假设。将采用体外和体内模型，其中计划利用蛋白质印迹技术以及基于流式细胞术的技术来绘制 CD95 信号网络。