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

• 批准号: 7960574
• 负责人: Joel Marvin Guthridge
• 金额: $ 12.59万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960574
• 关键词: Affect; African American; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; Biological; Biology; Calcium; Candidate Disease Gene; Cell Line; Cell Surface Receptors; Cells; Centers of Research Excellence; Clinical; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Disease; Exhibits; Funding; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genome; Grant; Immune system; Individual; Institution; Lupus; Measurable; Measurement; Molecular; Organism; Pathology; Pathway interactions; Patients; Phase; Phenotype; Phosphorylation; Population; Positioning Attribute; Proteins; Quantitative Genetics; Receptors, Antigen, B-Cell; Research; Research Personnel; Resources; Signal Pathway; Signal Transduction; Source; Structure; Symptoms; System; Systemic Lupus Erythematosus; Testing; Transformed Cell Line; United States National Institutes of Health; case control; crosslink; genetic analysis; genetic association; genetic variant; human disease; interest; molecular phenotype; protein function; response; trait

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 系统性红斑狼疮（SLE）是一种复杂的多基因自身免疫性疾病，具有多种临床症状。 寻找与该疾病相关的基因已经使用了许多补充方法；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背后的生物学原理。 生物体、免疫系统和环境影响的复杂性使我们无法关注基因组中编码的分子细节，这些细节影响对疾病发展很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。 B 细胞激活是自身抗体产生所必需的，而自身抗体是 SLE 相关病理学发展的关键。 我们怀疑，影响 B 细胞表面受体参与导致的 B 细胞信号传导关键蛋白的基因表达或功能的遗传多态性是导致狼疮患者观察到的 B 细胞反应改变的原因。 我们识别这些基因和多态性的方法要求我们首先定义系统的边界（B 细胞激活和控制）、可测量的效应（生物分子表型）并收集感兴趣群体的表型数据。 下一步将是通过数量性状关联分析来分析第一阶段的组合表型数据和独立收集的有关祖先信息遗传标记的遗传数据。 第三阶段是确定导致 B 细胞反应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 转化细胞系来确定 B 细胞信号通路的关键成分如何响应 B 细胞受体 (BCR) 交联。 我们已经证实，狼疮患者和对照的细胞也表现出改变的 B 细胞反应特征。 B 细胞特异性信号传导导致的细胞内钙反应、ERK1/2 磷酸化和 Lyn 磷酸化在这些细胞系中发生改变。 狼疮患者和对照细胞系之间的基因表达是不同的，并且已鉴定出一组可能与引起 B 细胞反应差异有关的基因/蛋白质。我们开始鉴定表征狼疮 B 细胞反应的关键分子表型。 现在，我们将重点关注这些途径的组成部分，同时扩大对 AA 狼疮病例和对照的其他 B 细胞系中这些分子表型的测量和分析。 我们正在检查初步基因表达分析中确定的各个候选基因，确认它们的表达，探索可能的多态性，并测试它们与狼疮的独立遗传关联。 我们有能力描述在选定的狼疮患者亚群中观察到的 B 细胞反应的候选功能差异，并建立利用定量遗传分析与 B 细胞系统中生物分子亚表型相结合的能力的能力。