Delineation of genetic pathways to lupus pathogenesis

狼疮发病机制的遗传途径的描述

• 批准号: 6534539
• 负责人: KUI LIU
• 金额: $ 4.57万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6534539
• 关键词: B lymphocyte; disease /disorder model; functional /structural genomics; gene expression; genetic mapping; laboratory mouse; microarray technology; molecular pathology; pathologic process; protooncogene; systemic lupus erythematosus

DESCRIPTION (provided by the applicant): Systemic lupus erythematosus (SLE) is characterized by the presence of anti-nuclear antibodies (ANA) directed against naked DNA and entire nucleosomes. Development of congenic mouse models carrying lupus susceptibility gene intervals has provided powerful tools for studying the mechanism of lupus pathogenesis. Sle1 mediates the loss of tolerance to nuclear antigens and the initiation of autoimmunity. Our recent study demonstrated that Sle1 mediates the abnormal expression of several genes, including the c-myc protooncogene, that control B-cell activation and proliferation. We hypothesize that autoreactive B-cells are generated from B-cell populations that have aberrant c-myc expression. We propose to identify the mechanisms leading to the aberrant c-myc expression and to characterize the B-cell populations that have aberrant c-myc expression in B6.Sle1 mice. We also propose to use powerful, microarray-based approaches to identify the molecular mechanisms by which Sle1 and S1e3 interact to cause lupus. Furthermore, we propose to identify lupus susceptibility gene(s) in the S1e3 interval using fine mapping in combination with functional genomics. By identifying the lupus susceptibility genes and the molecules involved in the pathogenesis, we can select candidate therapeutic targets for curing lupus.

描述（由申请人提供）：系统性红斑狼疮（SLE）是 其特征在于存在抗核抗体（ANA）， 裸DNA和整个核小体。同种小鼠携带病毒模型的建立 狼疮易感基因间隔为研究 狼疮的发病机制。sle 1介导了耐受性的丧失， 核抗原和自身免疫的启动。我们最近的研究 表明Sle 1介导了几个基因的异常表达， 包括控制B细胞活化的c-myc原癌基因， 增殖我们假设自身反应性B细胞是由 具有异常c-myc表达的B细胞群体。我们建议确定 探讨c-myc基因表达异常的机制， B6.Sle 1小鼠中具有异常c-myc表达的B细胞群。我们也 建议使用强大的，基于微阵列的方法来识别分子 Sle 1和S1 e3相互作用导致狼疮的机制。而且我们 建议在S1 e3间期使用以下方法识别狼疮易感基因： 精细定位与功能基因组学相结合。通过识别狼疮 易感基因和参与发病机制的分子，我们可以 选择治疗狼疮的候选治疗靶点。