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:
  • 金额:
    $ 19万
  • 依托单位:
  • 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

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,在动物模型和人类中被认为是导致自身免疫性疾病的一个因素。在动物模型中,对汞的易感性受到基因的限制,但由于人类群体的异质性,很难建立人类的遗传限制。然而,由于汞广泛分布在环境中,汞是一个很好的例子,其中暴露于环境因素已与自身免疫性疾病的发展,并在外源性因子与选择性遗传背景相互作用,导致免疫性疾病。不幸的是,在这个时候,汞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用作暴露特征,以确定汞在80多种影响人类的自身免疫性疾病中的广泛参与。最近,人们越来越多地认识到B细胞参与自身免疫性疾病。已知B细胞受体(BCR)信号通路中的缺陷破坏中枢耐受性,并因此与自身免疫性疾病相关。林恩是Src家族蛋白酪氨酸激酶,已显示其密切参与BCR信号传导途径的起始和调节。林恩功能通过几个不同酪氨酸残基的磷酸化来控制。在初步的实验中,研究人员采用先进的蛋白质组学和流式细胞术的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假设,汞暴露后改变的林恩磷酸化特征和功能可能是介导汞暴露后B细胞免疫毒性的关键相关现象,以及汞中毒个体中自身免疫B细胞库的出现。在这种情况下,B细胞中特异性林恩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。研究人员现在建议在初步实验的基础上进行扩展。他们将利用对汞中毒具有不同但明确的遗传易感性的小鼠品系,并采用互补蛋白质组学和荧光磷酸流式细胞术方法直接研究汞暴露改变林恩磷酸化特征和功能的能力,从而干扰BCR信号转导,并最终破坏脾B细胞的中心耐受性。

项目成果

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ALLEN J ROSENSPIRE其他文献

ALLEN J ROSENSPIRE的其他文献

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{{ truncateString('ALLEN J ROSENSPIRE', 18)}}的其他基金

Understanding the connection between exposure to mercury, auto-immunity and tolerance in B cells.
了解汞暴露、自身免疫和 B 细胞耐受性之间的联系。
  • 批准号:
    10220035
  • 财政年份:
    2018
  • 资助金额:
    $ 19万
  • 项目类别:
Understanding the connection between exposure to mercury, auto-immunity and tolerance in B cells.
了解汞暴露、自身免疫和 B 细胞耐受性之间的联系。
  • 批准号:
    9770861
  • 财政年份:
    2018
  • 资助金额:
    $ 19万
  • 项目类别:
Understanding the connection between exposure to mercury, auto-immunity and tolerance in B cells.
了解汞暴露、自身免疫和 B 细胞耐受性之间的联系。
  • 批准号:
    9979868
  • 财政年份:
    2018
  • 资助金额:
    $ 19万
  • 项目类别:
Understanding the connection between exposure to mercury, auto-immunity and tolerance in B cells
了解汞暴露、自身免疫和 B 细胞耐受性之间的联系
  • 批准号:
    9539264
  • 财政年份:
    2017
  • 资助金额:
    $ 19万
  • 项目类别:
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:
    9061041
  • 财政年份:
    2014
  • 资助金额:
    $ 19万
  • 项目类别:
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
  • 财政年份:
    2014
  • 资助金额:
    $ 19万
  • 项目类别:
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
  • 财政年份:
    2012
  • 资助金额:
    $ 19万
  • 项目类别:
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:
    8259913
  • 财政年份:
    2012
  • 资助金额:
    $ 19万
  • 项目类别:
Analysis of B Cell Receptor Signals Modified by Mercury
汞修饰的 B 细胞受体信号分析
  • 批准号:
    8111865
  • 财政年份:
    2010
  • 资助金额:
    $ 19万
  • 项目类别:
Analysis of B Cell Receptor Signals Modified by Mercury
汞修饰的 B 细胞受体信号分析
  • 批准号:
    7962343
  • 财政年份:
    2010
  • 资助金额:
    $ 19万
  • 项目类别:

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