Functional Relationships Between the Lupus Susceptibility Loci Lyn and Ets1

狼疮易感性位点 Lyn 和 Ets1 之间的功能关系

基本信息

  • 批准号:
    8283350
  • 负责人:
  • 金额:
    $ 16.86万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-04-01 至 2014-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nuclear antigens, autoantibody production, and immune complex mediated damage to multiple organs. Mice deficient in two SLE susceptibility genes, the tyrosine kinase Lyn and the transcription factor Ets1, have remarkably similar phenotypes. These include B cell hyperactivity, early accumulation of IgM-secreting plasma cells, production of IgG autoantibodies, and immune complex deposition in the kidney. Preliminary results indicate that Ets1 expression is dramatically reduced in Lyn-/- B cells. Furthermore, decreased expression of both genes has been observed in PBMCs of SLE patients. Given that Ets1 is known to limit B cell terminal differentiation, we hypothesize that Lyn normally restricts the formation of autoreactive plasma cells by promoting expression of Ets1 in B cells. We propose to characterize the functional interaction between Lyn and Ets1 via the following Specific Aims: 1) to define the mechanism by which Lyn controls Ets1 expression, and 2) to determine the consequences of reduced Ets1 expression for the plasma cell accumulation and autoimmune phenotypes of Lyn-/- mice. These studies will define and characterize a previously unidentified interaction between two SLE susceptibility loci, potentially illuminating a novel pathway that can be targeted therapeutically. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease characterized by the production of antibodies against oneself, which then cause tissue damage. We propose to test the idea that two lupus susceptibility genes, Lyn and Ets1, work together in a molecular pathway to prevent the differentiation of B cells into autoantibody producing cells. Our studies may suggest ideas to allow targeting of this novel pathway with newly-designed therapeutic regimens designed to limit autoantibody secretion.
描述(申请人提供):系统性红斑狼疮(SLE)的特征是对核抗原的耐受性丧失,自身抗体的产生,以及免疫复合体介导的多器官损伤。缺乏两个SLE易感基因的小鼠,酪氨酸激酶Lyn和转录因子Ets1,具有非常相似的表型。这些症状包括B细胞过度活跃、分泌IgM的浆细胞的早期积聚、免疫球蛋白自身抗体的产生以及免疫复合体在肾脏中的沉积。初步结果表明,在Lyn-/-B细胞中,Ets1的表达显著降低。此外,在SLE患者的PBMC中观察到这两种基因的表达都降低了。鉴于已知Ets1可以限制B细胞的终末分化,我们假设Lyn通常通过促进B细胞中Ets1的表达来限制自身反应性浆细胞的形成。我们建议通过以下特定目的来描述Lyn和Ets1之间的功能相互作用:1)确定Lyn控制Ets1表达的机制,以及2)确定Ets1表达减少对Lyn-/-小鼠浆细胞聚集和自身免疫表型的影响。这些研究将定义和描述两个SLE易感基因座之间以前未知的相互作用,潜在地照亮一条可以作为治疗靶点的新途径。 公共卫生相关性:系统性红斑狼疮(SLE)是一种潜在的致命性自身免疫性疾病,其特征是产生针对自身的抗体,然后导致组织损伤。我们建议测试两个狼疮易感基因Lyn和Ets1在分子途径中共同作用的想法,以防止B细胞分化为产生自身抗体的细胞。我们的研究可能会提出一些想法,允许通过新设计的治疗方案来靶向这一新的途径,以限制自身抗体的分泌。

项目成果

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Anne B Satterthwaite其他文献

Anne B Satterthwaite的其他文献

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{{ truncateString('Anne B Satterthwaite', 18)}}的其他基金

T-bet expressing B cells in autoimmunity
T-bet 在自身免疫中表达 B 细胞
  • 批准号:
    10378006
  • 财政年份:
    2021
  • 资助金额:
    $ 16.86万
  • 项目类别:
T-bet expressing B cells in autoimmunity
T-bet 在自身免疫中表达 B 细胞
  • 批准号:
    10231925
  • 财政年份:
    2021
  • 资助金额:
    $ 16.86万
  • 项目类别:
PIK3IP1 in B Cell Development and Function
PIK3IP1 在 B 细胞发育和功能中的作用
  • 批准号:
    9305835
  • 财政年份:
    2016
  • 资助金额:
    $ 16.86万
  • 项目类别:
Attenuation of Lupus by Foxo3
Foxo3 减弱狼疮作用
  • 批准号:
    9113494
  • 财政年份:
    2015
  • 资助金额:
    $ 16.86万
  • 项目类别:
Attenuation of Lupus by Foxo3
Foxo3 减弱狼疮作用
  • 批准号:
    8912817
  • 财政年份:
    2015
  • 资助金额:
    $ 16.86万
  • 项目类别:
Inhibitory receptors in early B cell development
早期 B 细胞发育中的抑制性受体
  • 批准号:
    8523779
  • 财政年份:
    2012
  • 资助金额:
    $ 16.86万
  • 项目类别:
Inhibitory receptors in early B cell development
早期 B 细胞发育中的抑制性受体
  • 批准号:
    8400223
  • 财政年份:
    2012
  • 资助金额:
    $ 16.86万
  • 项目类别:
Functional Relationships Between the Lupus Susceptibility Loci Lyn and Ets1
狼疮易感性位点 Lyn 和 Ets1 之间的功能关系
  • 批准号:
    8449070
  • 财政年份:
    2012
  • 资助金额:
    $ 16.86万
  • 项目类别:
Mechanisms of the suppression of autoimmunity
抑制自身免疫的机制
  • 批准号:
    8274815
  • 财政年份:
    2011
  • 资助金额:
    $ 16.86万
  • 项目类别:
Mechanisms of the suppression of autoimmunity
抑制自身免疫的机制
  • 批准号:
    7628045
  • 财政年份:
    2008
  • 资助金额:
    $ 16.86万
  • 项目类别:

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