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

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，在动物模型和人群中，低暴露水平已被认为是导致认知障碍、炎症和自身免疫性疾病的一个因素。然而，对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更能抵抗汞的有害影响。由于鱼类含有特别高水平的n-3多不饱和脂肪酸（n-3 PUFA），因此有人认为，低水平汞中毒的有害影响可以通过饮食摄入n-3 PUFA来抵消。目前尚不清楚n-3 PUFA如何与汞相互作用，从而防止低水平中毒的有害影响。然而，我们之前已经表明，低水平汞中毒的一个后果是Fas （CD95）介导的信号转导和激活诱导的免疫系统细胞死亡（AICD）被抑制。CD95信号和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信号的衰减与动物和人类中以淋巴结病和狼疮样炎症性免疫病理为特征的自身免疫性增生性综合征有关。另一方面，一些研究人员报道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，也有报道称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。这些发现导致了一种假设，即高水平的饮食输入n-3 PUFA可以通过恢复CD95在激活的汞中毒淋巴细胞中正确发出AICD信号的能力来防止低水平汞中毒的有害影响。这一提议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western blotting技术以及基于流式细胞术的技术来绘制CD95信号网络。

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.