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

• 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
• 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

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）是一种有效的神经毒素和免疫调节剂，在低暴露水平下，在动物模型和人类种群中，在低暴露水平上已被视为导致认知障碍以及对炎症和自身免疫性疾病的因素。但是，对也消耗大量鱼类的低水平HG醉酒种群的流行病学研究似乎表明，这些人群对HG的有害影响更具耐药性，而不是消耗大量鱼类的HG醉酒种群。由于鱼具有特别高的N-3多不饱和脂肪酸（N-3 PUFA），因此有人提出，饮食摄入N-3 PUFA可能会抵消低水平HG中毒的有害影响。目前，对N-3 PUFA如何与HG相互作用尚无机械理解，以防止低水平中毒的有害影响。但是，我们先前已经表明，低水平Hg中毒的结果是，免疫系统中FAS（CD95）介导的信号转导和激活诱导的细胞死亡（AICD）是抑郁症的。 CD95信号传导和AICD在生理上对于维持免疫系统稳态在生理上很重要，并且众所周知，CD95信号传导的衰减与动物和人类中狼疮性炎性疾病和狼疮样炎症性免疫病理学相关。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几种自身免疫性疾病。值得注意的是，还报道了N-3 PUFA的抗炎特性可能与它们增强CD95信号传导和AICD的能力有关。这些发现导致了以下假设：N-3 PUFA的高饮食输入将通过恢复CD95在激活但HG陶醉的淋巴细胞中正确向AICD发出适当信号的能力，从而防止低水平HG中毒的有害作用。该建议旨在严格检验该假设。将采用体外和体内模型，该计划将使用蛋白质印迹技术，以及基于流式细胞仪的技术来映射CD95信号网络。