OK COBRE: GENETICS OF B LYMPHOCYTE SIGNALING IN LUPUS

OK COBRE:狼疮 B 淋巴细胞信号传导的遗传学

基本信息

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Systemic lupus erythematosus (SLE) is a complex, multigenic autoimmune disease with diverse clinical symptoms. The search for the genes associated with the disease has utilized numerous complementary approachs; however, we still do not have a complete understanding of the biology behind how SLE-associated candidate genes actually cause the human disease. The complexity of the organism, the immune system and the environmental influences cloud our ability to focus on the molecular details encoded in the genome that affect the biological structures and functions in proteins important to the development of disease. B cells are now recognized as central players in the development of SLE. B cell activation is required for development of autoantibodies, which are key to the development of SLE associated pathology. We suspect genetic polymorphisms that affect the gene expression or function of proteins critical in controlling B cell signaling resulting from B cell surface receptor engagement are responsible for altered B cell responses observed in lupus patients. Our approach to identify these genes and polymorphisms requires that we first define the boundaries of the system (B cell activation and control), the measurable effects (biomolecular phenotypes) and collect phenotypic data on the population of interest. The next step would be to analyze the combined phenotypic data from phase 1 and independently collected genetic data on ancestral informative genetic markers by Quantitative Trait Association analysis. Phase 3 is to identify genetic variants responsible for altered B cell response phenotypes and determine the biomolecular pathways and mechanisms affected. We have used EBV-transformed cell lines derived from African-American (AA) lupus patients and controls to identify how key components of the B cell signaling pathways respond to B cell receptor (BCR) cross-linking. We have confirmed that cells from lupus patients and controls also exhibit altered B cell response profiles. Intracellular calcium responses, ERK1/2 phosphorylation, and Lyn phosphorylation upon B cell specific signaling are altered in these cell lines. Gene expression between cell lines from lupus patients and controls is different and has identified a set of genes/proteins which are likely involved in causing differences in B cell responses. We are beginning to identify key molecular phenotypes that characterize a lupus B cell response. We will now focus on components of those pathways as we expand our measurement and analysis of these molecular phenotypes in additional B cell lines from AA lupus cases and controls. We are examining individual candidate genes identified in the preliminary gene expression analysis, confirming their expression, exploring possible polymorphisms, and testing these for independent genetic association with lupus. We are well positioned to describe candidate functional differences in B cell responses observed in selected subsets of lupus patients and also to build the ability to exploit the power of quantitative genetic analysis in combination with biomolecular sub-phenotypes in the B cell system.
这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者(PI)可能从另一个NIH来源获得了主要资金, 因此可以在其他CRISP条目中表示。所列机构为 研究中心,而研究中心不一定是研究者所在的机构。 系统性红斑狼疮(SLE)是一种复杂的多基因自身免疫性疾病,临床症状多样。 寻找与疾病相关的基因已经利用了许多互补的方法;然而,我们仍然没有完全了解SLE相关候选基因实际上如何导致人类疾病的生物学。 生物体、免疫系统和环境影响的复杂性使我们无法专注于基因组中编码的分子细节,这些分子细节影响对疾病发展至关重要的蛋白质的生物结构和功能。 B细胞现在被认为是SLE发展的核心参与者。自身抗体的产生需要B细胞活化,而自身抗体是SLE相关病理学发展的关键。 我们怀疑遗传多态性影响基因表达或蛋白质的功能,这些蛋白质在控制B细胞信号传导中起关键作用,这些信号传导是由B细胞表面受体接合引起的,这些基因多态性是狼疮患者中观察到的B细胞反应改变的原因。 我们鉴定这些基因和多态性的方法要求我们首先确定系统的边界(B细胞激活和控制)、可测量的效应(生物分子表型)并收集感兴趣人群的表型数据。 下一步将是通过数量性状关联分析来分析来自第1阶段的组合表型数据和独立收集的关于祖先信息遗传标记的遗传数据。 第3阶段是鉴定导致B细胞应答表型改变的遗传变异,并确定受影响的生物分子途径和机制。 我们已经使用来自非裔美国人(AA)狼疮患者和对照的EBV转化细胞系来鉴定B细胞信号通路的关键组分如何响应B细胞受体(BCR)交联。 我们已经证实,狼疮患者和对照组的细胞也表现出改变的B细胞反应谱。 在这些细胞系中,细胞内钙应答、ERK 1/2磷酸化和B细胞特异性信号传导后的林恩磷酸化发生改变。 来自狼疮患者和对照的细胞系之间的基因表达是不同的,并且已经鉴定了一组可能参与引起B细胞应答差异的基因/蛋白质。我们开始确定狼疮B细胞反应的关键分子表型。 我们现在将集中在这些途径的组成部分,因为我们扩大我们的测量和分析这些分子表型在额外的B细胞系从AA狼疮病例和对照。 我们正在检查初步基因表达分析中确定的单个候选基因,确认它们的表达,探索可能的多态性,并测试这些与狼疮的独立遗传关联。 我们很好地定位于描述在选定的狼疮患者亚群中观察到的B细胞应答中的候选功能差异,并且还建立了利用定量遗传分析结合B细胞系统中的生物分子亚表型的能力。

项目成果

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Joel Marvin Guthridge其他文献

Joel Marvin Guthridge的其他文献

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{{ truncateString('Joel Marvin Guthridge', 18)}}的其他基金

Mechanisms of New-Onset Autoimmunity/Longitudinal Immune Systems Analysis (MONA-LISA)
新发自身免疫/纵向免疫系统分析(MONA-LISA)的机制
  • 批准号:
    10655219
  • 财政年份:
    2023
  • 资助金额:
    $ 13.73万
  • 项目类别:
Accelerating Medicines Partnership-Autoimmune and Immunologic Disease Tissue Research Core Admin Supplement: Preclinical Studies in Sjogren's
加速药物合作 - 自身免疫和免疫疾病组织研究核心管理补充:干燥病的临床前研究
  • 批准号:
    10834635
  • 财政年份:
    2022
  • 资助金额:
    $ 13.73万
  • 项目类别:
Accelerating Medicines Partnership-Autoimmune and Immunologic Disease Tissue Research Core
加速药物合作——自身免疫和免疫疾病组织研究核心
  • 批准号:
    10687729
  • 财政年份:
    2022
  • 资助金额:
    $ 13.73万
  • 项目类别:
Accelerating Medicines Partnership-Autoimmune and Immunologic Disease Tissue Research Core
加速药物合作——自身免疫和免疫疾病组织研究核心
  • 批准号:
    10452026
  • 财政年份:
    2022
  • 资助金额:
    $ 13.73万
  • 项目类别:
Accelerating Medicines Partnership-Autoimmune and Immunologic Disease Tissue Research Core
加速药物合作——自身免疫和免疫疾病组织研究核心
  • 批准号:
    10596177
  • 财政年份:
    2022
  • 资助金额:
    $ 13.73万
  • 项目类别:
Human Phenotyping Core
人类表型核心
  • 批准号:
    10478211
  • 财政年份:
    2018
  • 资助金额:
    $ 13.73万
  • 项目类别:
Human Phenotyping Core
人类表型核心
  • 批准号:
    10016171
  • 财政年份:
    2018
  • 资助金额:
    $ 13.73万
  • 项目类别:
Human Phenotyping Core
人类表型核心
  • 批准号:
    10704390
  • 财政年份:
    2018
  • 资助金额:
    $ 13.73万
  • 项目类别:
Ikaros family genes and lupus susceptibility across ethnically diverse populations
Ikaros 家族基因和不同种族人群的狼疮易感性
  • 批准号:
    9770772
  • 财政年份:
    2018
  • 资助金额:
    $ 13.73万
  • 项目类别:
Human Phenotyping Core
人类表型核心
  • 批准号:
    10251965
  • 财政年份:
    2018
  • 资助金额:
    $ 13.73万
  • 项目类别:

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扩大参与研究:了解教师对 HBCU 的非裔美国 STEM 学生提供职业建议的态度、能力和看法
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