OK COBRE: FC RECEPTOR B LYMPHOCYTE SIGNALING IN LUPUS

OK COBRE：狼疮中 FC 受体 B 淋巴细胞信号传导

• 批准号: 6972160
• 负责人: Joel Marvin Guthridge
• 金额: $ 44.44万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6972160
• 关键词: B lymphocyte; CD antigens; antibody receptor; autoimmunity; biological signal transduction; clinical research; disease /disorder etiology; female; gene expression; genetic polymorphism; genetic susceptibility; genotype; human data; human genetic material tag; immunogenetics; leukocyte activation /transformation; linkage mapping; microarray technology; patient oriented research; protein structure function; receptor expression; systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex, multigenic autoimmune disease. A strong genetic linkage at 1q23 and association results with lupus reveal the importance of the low-affinity Fc receptor family as genes for lupus susceptibility. Fc-gammaRIIb knock-out mouse studies and two separate, unpublished genetic association studies have implicated the Fc-gammaRIIb as a susceptibility gene for lupus. A polymorphism in the transmembrane domain of Fc-gammaRIIb alters lipid raft association and influences intracellular calcium and CD19 phosphorylation following B cell activation. Two promoter polymorphisms increased Fc-gammaRIIb expression and caused decreased intracellular calcium levels and decreased apoptosis. The effect of the Fc-gammaRIIb knockout in the mouse and the incompletely described enhancing effects of the human Fc-gammaRIIb polymorphisms strongly suggest possible involvement of Fc-gammaRIIb in lupus development by a yet to be described mechanism that we suspect involves the receptor activation pathway. The previous studies relied upon in vitro assays of recombinant Fc-gammaRIIb molecules transfected into model cell systems for characterization of Fc receptor functions. Although informative, these data do not allow us to fully appreciate the functional differences of these polymorphic Fc-gammaRIIb molecules in cells from actual lupus patients or matched normal controls. We will approach these important issues by utilizing the genetic and cellular resources from the OMRF lupus genetics group to directly assess the functional differences in Fc-gammaRIIb in B cells derived from lupus patients and normal matched controls. We propose that polymorphisms in both the Fc-gammaRIIb protein and the Fc-gammaRIIb promoter that alter Fc-gammaRIIb expression will result in functional differences in signaling through this receptor. We anticipate that these differences will be reflected in differences in B cell signaling responses upon engagement of the Fc-gammaRIIb, of the B cell receptor, or of co-engagement of both receptors. We will analyze B cell responses associated with Fc-gammaRIIb related signaling pathways in lupus cases and controls selected by strong 1q23 linkage and group them into signaling classes by type of B cell signaling responses resulting from Fc-gammaRIIb engagement. Genotypes of the signaling classes will be analyzed to determine if there is increased association with lupus. Gene expression or biochemical pathways associated with each signaling class will be assessed and used to identify genes that contribute to lupus susceptibility through epistatic or additive gene effects. Understanding the role of Fc-gammaRIIb in B cell activation will allow us to better explain lupus development and uncover novel therapeutic targets for this devastating disease.

全身性红斑狼疮（SLE）是一种复杂的多基因自身免疫性疾病。第1季度的强大遗传连锁和与狼疮的关联结果揭示了低亲和力FC受体家族作为狼疮易感性的基因的重要性。 FC-Gammariib敲除小鼠研究和两项独立的未发表的遗传关联研究已将FC-Gammariib作为狼疮的易感基因。 FC-Gammariib的跨膜结构域的多态性改变了脂质筏的关联，并影响细胞内钙和CD19 B细胞激活后的磷酸化。两种启动子多态性增加了FC-Gammariib的表达，并导致细胞内钙水平降低和凋亡降低。 FC-Gammariib敲除在小鼠中的影响以及人类FC-Gammariib多态性的不完全描述的增强作用强烈表明FC-Gammariib可能通过一种尚未描述的机制参与狼疮的发展。 我们怀疑涉及受体激活途径。先前的研究依赖于重组FC-Gammariib分子转染的体外测定，用于表征FC受体功能的模型细胞系统。尽管内容丰富，但这些数据不允许我们完全理解来自实际狼疮患者的细胞中这些多态性FC-Gammariib分子的功能差异或匹配正常对照。我们将通过利用OMRF狼疮遗传学组的遗传和细胞资源来直接评估来自狼疮患者的B细胞中FC-GammariiB的功能差异来解决这些重要问题。 和正常匹配的控件。我们提出，FC-Gammariib蛋白和FC-Gammariib启动子中的多态性都将改变FC-Gammariib的表达会导致通过该受体的信号传导的功能差异。我们预计，这些差异将反映在FC-GammariiB，B细胞受体或两种受体共同参与后B细胞信号反应的差异中。我们将分析与FC-GammariiB相关的信号通路相关的B细胞响应，以及由强1Q23链接选择的对照，并通过FC-Gammariib参与引起的B细胞信号响应的类型将其分组为信号类别。将分析信号传导类别的基因型，以确定与狼疮的关联是否增加。将评估与每个信号类别相关的基因表达或生化途径，并用于识别通过上毒或加性基因效应有助于狼疮易感性的基因。了解FC-GammariiB在B细胞激活中的作用将使我们更好地解释 狼疮的发育并发现了这种毁灭性疾病的新型治疗靶标。