Characterization of SLE Loci on Mouse Chromosome 1

小鼠 1 号染色体上 SLE 基因座的表征

• 批准号: 6876564
• 负责人: Laurence Morel
• 金额: $ 32.74万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876564
• 关键词: B lymphocyte; T lymphocyte; bone marrow; cellular pathology; disease /disorder model; gene expression; gene interaction; genetic mapping; genetic strain; genetic susceptibility; immune tolerance /unresponsiveness; laboratory mouse; leukocyte activation /transformation; microarray technology; molecular pathology; phenotype; recombinant DNA; systemic lupus erythematosus; tissue mosaicism

DESCRIPTION (provided by applicant): Sle1 is the strongest susceptibility locus in the NZM2410 mouse model of SLE. We have shown that it mediates the loss of tolerance to nuclear antigens, and that its expression is required for full reconstitution of the disease. In the process of developing a high resolution map of Sle 1, we have demonstrated that it corresponds to three loci, Sle1a, Sle1b, and Sle1 c. Each of these loci results in autoantibodies against nuclear antigens, but in a different profile of lymphocyte marker expression, suggesting that they belong to different functional pathways. In parallel with gene identification efforts being conducted on these genes, we propose to characterize how these loci contribute to SLE pathogenesis, either by themselves, in combinations with each other, or in combination with other SLE-susceptibility genes. This study is necessary because, in most cases, gene identification does not provide information on the mechanisms by which this given gene is involved in the disease process. In addition, analyses of polygenic autoimmune diseases have clearly shown that pathogenesis results from interactions between weak loci. We have developed during the initial funding of this proposal a unique model to dissect out these interactions based on gain of phenotype analyses. Our model now comprises a large collection of congenic strains that either contain small genomic intervals with a single susceptibility locus, or various combinations of them. We have also compiled a large database of tissues and phenotypes corresponding to these strains. This proposal has four specific aims: 1) To delineate the impact of Sle1a, Sle1b, and Sle1c on lymphocyte functions and to dissect the interactions between these loci. These experiments will combine characterization of B and T cell development associated with each locus, breeding of the uMT and Tcra null mutations to assess the impact of the Sle1 loci on intrinsic B and T cells defects, and bone marrow chimeras to analyze interactions; 2) To evaluate genetically and functionally Cr2 as candidate gene for Sle1c. We will generate recombinants to assess whether Sle1c co-segregate with Cr2, produce BM chimeras to localize the functional expression of Sle1c between B cells and FDC, and evaluate the role of Sle1c in anti-dsDNA tolerance by using the 3H9 sd-tg system; 3) To assess how Sle1a, Sle1b, and Sle1c interact with other SLE loci, using Ipr, Yaa, and Sles1 as models. We have shown that Sle1 co-expression with either Yaa or lpr results into a highly penetrant SLE, while Sles1 shuts down Sle1 phenotypes, and that each Sle1 locus engages into a different type of interaction with these loci. We propose to use this system to dissect the role and mechanism of interactions in SLE pathogenesis, using immunological characterization gene expression profiling, and a bone marrow chimera approach to trace the fate of B cells expressing a pathogenic combination of loci.; 4) To characterize two new susceptibility loci on chromosomes 10 and 11 and their interaction with Sle1. Two new susceptibility loci have been identified and we propose to combine them with Sle1 to characterize their contribution to the disease and to map their location. These experiments are part of a multi team effort to identity and characterize the genes responsible for a major SLE-susceptibility locus in order to be able to design therapeutic interventions on these genes and their functional pathways.

描述（由申请方提供）：Sle 1是SLE NZM 2410小鼠模型中最强的易感性基因座。我们已经表明，它介导的耐受性的损失，核抗原，其表达所需的疾病的完全重建。在开发Sle 1的高分辨率图谱的过程中，我们已经证明它对应于三个位点，Sle 1a，Sle 1b和Sle 1c。这些位点中的每一个导致针对核抗原的自身抗体，但在淋巴细胞标志物表达的不同概况中，表明它们属于不同的功能途径。在与这些基因进行基因鉴定工作的同时，我们建议表征这些位点如何有助于SLE发病机制，无论是通过自身，相互结合，或与其他SLE易感基因结合。这项研究是必要的，因为在大多数情况下，基因鉴定不能提供有关该特定基因参与疾病过程的机制的信息。此外，对多基因自身免疫性疾病的分析清楚地表明，发病机制是弱基因座之间相互作用的结果。我们已经开发了一个独特的模型，以解剖出这些相互作用的基础上获得的表型分析在最初的资金这个建议。我们的模型现在包括一个大的同类菌株，要么包含一个单一的易感性位点，或它们的各种组合的小基因组间隔的集合。我们还编制了一个大型数据库的组织和表型对应于这些菌株。本研究的目的有四：1）阐明Sle 1a、Sle 1b和Sle 1c对淋巴细胞功能的影响，并分析这些位点之间的相互作用。这些实验将结合联合收割机表征与每个基因座相关的B和T细胞发育，培育uMT和Tcra无效突变以评估Sle 1基因座对内在B和T细胞缺陷的影响，以及骨髓嵌合体以分析相互作用; 2）在遗传和功能上评估Cr2作为Sle 1c的候选基因。我们将产生重组体以评估Sle 1c是否与Cr 2共分离，产生BM嵌合体以定位Sle 1c在B细胞和FDC之间的功能表达，并通过使用3 H9 sd-tg系统评估Sle 1c在抗dsDNA耐受中的作用; 3）以Ipr、Yaa和Sle 1为模型评估Sle 1a、Sle 1 B b和Sle 1c如何与其他SLE基因座相互作用。我们已经表明，Sle 1与Yaa或lpr共表达导致高度外显的SLE，而Sle 1关闭Sle 1表型，并且每个Sle 1位点与这些位点进行不同类型的相互作用。 我们建议使用该系统来剖析SLE发病机制中相互作用的作用和机制，使用免疫学特征基因表达谱和骨髓嵌合体方法来追踪表达致病基因座组合的B细胞的命运。4)研究10号和11号染色体上两个新的易感基因座及其与Sle 1的相互作用。两个新的易感基因座已被确定，我们建议联合收割机他们与Sle 1的特点，他们的贡献，疾病和地图的位置。这些实验是多个团队努力识别和表征负责主要SLE易感性位点的基因的一部分，以便能够设计对这些基因及其功能途径的治疗干预。