The Role of Mercury Exposures in Disrupting Central Tolerance

汞暴露在破坏中枢耐受性方面的作用

基本信息

批准号：
8899551
负责人：
ALLEN J ROSENSPIRE
金额：
$ 19万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8899551
关键词：
Address Affect Animal Model Antigens Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B cell repertoire B-Lymphocytes Binding Biochemical Biological Markers Cell Lineage Cells Defect Development Disease susceptibility Environment Event Exposure to Family Genes Genetic Genetic Predisposition to Disease Goals Health Human Human Characteristics Immune Immune System Diseases Immune Tolerance Immune response Immune system Immunogenetics Immunomodulators Individual Intervention Intoxication Intrinsic factor Lead Link Lymphocyte Maps Mass Spectrum Analysis Mediating Mercury Molecular Molecular Abnormality Molecular Target Mouse Strains Mus Pathway interactions Phosphoproteins Phosphorylation Phosphotyrosine Population Predisposition Process Proliferating Protein Tyrosine Kinase Proteins Proteome Proteomics Receptor Signaling Receptors, Antigen, B-Cell Regulation Regulatory Pathway Research Research Personnel Risk Role Shapes Signal Pathway Signal Transduction Staging Suggestion Sulfhydryl Compounds Surveys System Techniques Technology Time Tyrosine Tyrosine Phosphorylation Work base central tolerance design environmental agent immune function immunotoxicity improved lyn protein-tyrosine kinase multiple reaction monitoring receptor research study translational study

项目摘要

DESCRIPTION (provided by applicant): Mercury (Hg) is a potent immunomodulator that has been implicated as a factor contributing to autoimmune disease in animal models as well as in humans. In animal models, susceptibility to Hg is genetically restricted, but genetic restriction i humans has been difficult to establish because of the heterogeneous nature of human populations. Nevertheless, because Hg is widely distributed in the environment, Hg is an excellent example of where exposure to an environmental agent has been associated with the development of autoimmune disease, and where an extrinsic agent interacts with selective genetic backgrounds to cause immunologic disease. Unfortunately at this time a mechanistic understanding of how Hg disrupts immune function remains elusive. Furthermore, while studies clearly demonstrate an association between Hg exposures and increased risk of autoimmune disease, there are currently no molecular biomarkers that can be utilized as an exposure signature to identify Hg involvement across the broad spectrum of the over 80 individually characterized autoimmune diseases which affect humans. Recently there has been increased appreciation of the involvement of B cells in autoimmune disease. Defects in the B Cell Receptor (BCR) signaling pathway are known to disrupt central tolerance and consequently to be associated with autoimmune disease. Lyn is a Src family protein tyrosine kinase which has been shown to be intimately involved in the initiation and regulation of the BCR signaling pathway. Lyn functionality is controlled through the phosphorylation of several different tyrosine residues. In preliminary experiments the investigators have employed advanced proteomic and multicolor phosphoflow cytometric approaches to investigate the interaction of Hg with mouse B cells. Results from these experiments have led them to hypothesize that an altered Lyn phosphorylation profile and functionality consequent to Hg exposure may be key interrelated phenomena mediating immuntoxicity of B cells which have been exposed to Hg, and the emergence of an autoimmune B cell repertoire in mercury intoxicated individuals. This being the case, the expression of specific Lyn phosphorylation profiles in B cells may be a useful exposure signature of Hg-induced autoimmunity in Hg exposed individuals. The investigators now propose to expand upon preliminary experiments. They will utilize mouse strains with different, but well defined genetic susceptibilities to Hg intoxication, and employ complementary proteomic and multicolor phosphoflow cytometric approaches to directly investigate the ability of Hg exposures to alter Lyn phosphophorylation profiles and functionality, so as to interfere with BCR signal transduction, and ultimately disrupt central tolerance in splenic B cells.

描述（由申请人提供）：汞 (Hg) 是一种有效的免疫调节剂，已被认为是导致动物模型和人类自身免疫性疾病的一个因素。在动物模型中，汞的易感性受到遗传限制，但由于人类群体的异质性，很难确定人类的遗传限制。然而，由于汞广泛分布在环境中，汞是暴露于环境因素与自身免疫性疾病的发展相关以及外在因素与选择性遗传背景相互作用导致免疫疾病的一个很好的例子。不幸的是，目前对汞如何破坏免疫功能的机制尚不清楚。此外，虽然研究清楚地证明汞暴露与自身免疫性疾病风险增加之间存在关联，但目前还没有分子生物标志物可以用作暴露特征来识别汞参与广泛的 80 多种单独表征的自身免疫性疾病，这些疾病影响人类。最近，人们越来越认识到 B 细胞参与自身免疫性疾病。众所周知，B 细胞受体 (BCR) 信号通路的缺陷会破坏中枢耐受性，从而与自身免疫性疾病相关。 Lyn 是一种 Src 家族蛋白酪氨酸激酶，已被证明与 BCR 信号通路的启动和调节密切相关。 Lyn 功能是通过几个不同酪氨酸残基的磷酸化来控制的。在初步实验中，研究人员采用先进的蛋白质组学和多色磷流式细胞术方法来研究汞与小鼠 B 细胞的相互作用。这些实验的结果使他们推测，汞暴露导致的 Lyn 磷酸化谱和功能的改变可能是介导暴露于汞的 B 细胞免疫毒性的关键相关现象，以及汞中毒中自身免疫 B 细胞库的出现个人。在这种情况下，B 细胞中特定 Lyn 磷酸化谱的表达可能是汞暴露个体中汞诱导的自身免疫的有用暴露特征。研究人员现在建议扩大初步实验。他们将利用具有不同但明确的汞中毒遗传易感性的小鼠品系，并采用互补的蛋白质组学和多色磷流式细胞术方法直接研究汞暴露改变 Lyn 磷酸化谱和功能的能力，从而干扰 BCR 信号转导，并最终破坏脾 B 细胞的中枢耐受性。