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）是一种强效神经毒素和免疫调节剂，在低暴露水平下，在动物模型和人群中被认为是导致认知障碍以及炎症和自身免疫性疾病的一个因素。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，这些人群对汞的有害影响的抵抗力比不食用大量鱼类的同样汞中毒人群更强。由于鱼类的n-3多不饱和脂肪酸（n-3 PUFA）含量特别高，因此有人认为，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多不饱和脂肪酸如何与汞相互作用以防止低浓度中毒的有害影响，还没有一种机制上的理解。然而，我们以前已经表明，低水平汞中毒的一个后果是，Fas（CD 95）介导的信号转导和激活诱导的细胞死亡（AICD）在免疫系统中被抑制。CD 95信号传导和AICD在维持免疫系统稳态中是生理学上重要的，并且众所周知，CD 95信号传导的减弱与动物和人类中以淋巴结病和狼疮样炎性免疫病理学为特征的自身免疫增殖综合征相关。另一方面，一些研究者报道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的抗炎特性可能与其增强CD 95信号传导和AICD的能力有关。这些研究结果导致的假设，高饮食输入的n-3多不饱和脂肪酸将防止有害影响的低水平汞中毒恢复的能力，CD 95正确的信号AICD在激活，但汞中毒的淋巴细胞。本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CD 95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.