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

• 批准号: 8770404
• 负责人: ALLEN J ROSENSPIRE
• 金额: $ 22.8万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770404
• 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; 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; public health relevance; receptor; research study; translational study

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，被牵涉到动物模型和人类中自身免疫性疾病的一个因素。在动物模型中，对HG的易感性受到遗传限制，但是由于人类种群的异质性质，我很难建立遗传限制。然而，由于HG在环境中广泛分布，因此HG是一个很好的例子，即暴露于环境剂与自身免疫性疾病的发展有关，以及外在剂与选择性遗传背景相互作用以引起免疫疾病的地方。不幸的是，目前，对HG如何破坏免疫功能的机械理解仍然难以捉摸。此外，虽然研究清楚地表明，HG暴露与自身免疫性疾病的风险增加之间存在关联，但目前尚无分子生物标志物可以用作暴露签名来识别80多种超过80种单独表征的自身免疫性疾病的hg参与，这些疾病影响了人类。最近，人们对B细胞参与自身免疫性疾病的参与增加了。 B细胞受体（BCR）信号通路中的缺陷已知会破坏中心耐受性，因此与自身免疫性疾病有关。 Lyn是一种SRC家族蛋白酪氨酸激酶，已证明与BCR信号通路的启动和调控密切相关。 LYN功能通过几种不同酪氨酸残基的磷酸化来控制。在初步实验中，研究人员采用了先进的蛋白质组学和多色磷脂细胞仪方法来研究HG与小鼠B细胞的相互作用。这些实验的结果导致他们假设他们的LYN磷酸化谱和HG暴露导致的功能可能是关键的相互关联的现象，介导已暴露于HG的B细胞的免疫毒性，并且出现了自身免疫性B细胞在毒性个体中的自身免疫性B细胞库。在这种情况下，B细胞中特定的LYN磷酸化谱的表达可能是HG诱导的HG暴露个体自身免疫性的有用暴露特征。研究人员现在建议扩大初步实验。 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.