LUPUS GENES AND B-CELL SIGNALING

狼疮基因和 B 细胞信号传导

• 批准号: 7653974
• 负责人: CHANDRA MOHAN
• 金额: $ 35.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653974
• 关键词: Abbreviations; Alleles; Antibodies; Autoantibodies; B-Lymphocytes; Backcrossings; Binding; Bone Marrow; Candidate Disease Gene; Cells; Chromatin; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 7; Co-Immunoprecipitations; Congenic Mice; Congenic Strain; Development; Disease; Exhibits; Family member; Figs - dietary; First Degree Relative; Gene Dosage; Genes; Genetic; Genetic Models; Glomerulonephritis; Histones; Human; Immunoglobulin G; Individual; Kidney; Learning; Lupus; Lupus Erythematosus; Lupus Nephritis; Lymphocyte; MAP Kinase Gene; Mature B-Lymphocyte; Modeling; Molecular; Mus; Mutation; Myeloid Cells; NZW Mouse; Nephritis; Nuclear; Nucleosomes; Pathogenesis; Pathway interactions; Patients; Phenotype; Phenylalanine; Protein Isoforms; Receptors, Antigen, B-Cell; SLEB1 gene; SLEB3 gene; STAT3 gene; STAT5A gene; Severity of illness; Signal Pathway; Signal Transduction; Staging; Staining method; Stains; Susceptibility Gene; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Tyrosine; Variant; anti-IgG; base; cell type; congenic; drug induced lupus; effective therapy; human FRAP1 protein; human disease; insight; mouse model; novel; public health relevance; sle1/sle3 gene

DESCRIPTION (provided by applicant): Sle1 on murine chromosome 1 and Sle3 on murine chromosome 7 represent 2 of the strongest loci for lupus in the NZM2410 mouse model. To understand how these loci contribute to lupus, these disease loci have been backcrossed onto the relatively normal C57BL/6 background as congenic intervals. Whereas B6 mice are healthy, B6.Sle1 mice develop mild lupus, and B6.Sle1.Sle3 bicongenic mice develop severe lupus nephritis. We have recently documented that mature B-cells in these congenics exhibit progressive activation of multiple signaling pathways, including the AKT/mTOR axis, various MAPK pathways, NFkB, STAT3, STAT5, and various Bcl-2 family members, with the levels of activation correlating well with disease severity and susceptibility gene dosage. Importantly, the activation of some of these axes, notably NFkB and STAT3, were particularly pronounced in bicongenic mice with severe lupus, but not in B6.Sle1 mice. Whether the activation of any of these signaling pathways is necessary or sufficient for disease is not known. We hypothesize that NFkB and STAT3 activation is essential for the pathogenesis of lupus. This will be tested using a genetic approach in Aim 2 and a pharmacological approach in Aim 3. Though the culprit gene for Sle3 remains unknown, we have learned that the candidate gene for the strongest sub-locus within Sle1, namely SLAMF6/Ly108, functions in a B-cell intrinsic fashion to breach early B-cell tolerance. Presently, the molecular mechanisms through which Ly108 might breach tolerance remain unclear. We hypothesize that polymorphic variants of Ly108 may breach B- cell tolerance by engaging different signaling pathways within immature B-cells. This hypothesis will be tested in Aim 1. Collectively, these studies have important implications towards the mechanistic origins o systemi lupus erythematosus and how it is managed therapeutically. PUBLIC HEALTH RELEVANCE: We do not have a clear understanding of which signaling pathways within cells are most activated in different stages of lupus. Using novel genetically simplified mouse models, the proposed study aims to define the precise molecular contributions of different cell types in lupus. These studies will also ascertain if 2 particular molecules activated in lupus lymphocytes are essential for disease. Uncovering essential nodes in lupus pathogenesis using these novel genetic models are likely to pave the way towards more effective therapy in lupus targeting critical signaling nodes.

描述（由申请人提供）：鼠染色体1上的SLE1和鼠染色体7上的SLE3代表NZM2410鼠标模型中狼疮的最强基因座的2个。为了了解这些基因座如何对狼疮的贡献，这些疾病基因座作为先天的间隔已被反向跨越相对正常的C57BL/6背景。尽管B6小鼠是健康的，但B6.SLE1小鼠会出现轻度狼疮，而B6.SLE1.SLE3双胞胎小鼠出现严重的狼疮性肾炎。我们最近记录了这些兴趣的成熟B细胞表现出多种信号通路的逐步激活，包括AKT/MTOR轴，各种MAPK途径，NFKB，NFKB，STAT3，STAT3，STAT5和各种BCL-2家族成员，与疾病的严重程度和易感性基因剂量相关。重要的是，其中一些轴的激活，尤其是NFKB和STAT3，在具有严重狼疮的双胞胎小鼠中特别明显，但在B6.SLE1小鼠中却没有。这些信号通路中的任何一种是必需的还是足以使疾病的激活。我们假设NFKB和STAT3激活对于狼疮的发病机理至关重要。这将在AIM 2中使用遗传学方法和AIM 3中的药理学方法进行测试。尽管SLE3的罪魁祸首基因仍然未知，但我们了解到，SLE1中最强的子核心的候选基因，即SLAMF6/LY108，即SLAMF6/LY108，即B-Cell固有的固有方式，可突破B-Cell早期耐受性。目前，LY108可能违反耐受性的分子机制尚不清楚。我们假设LY108的多态性变体可能通过在未成熟的B细胞中参与不同的信号通路来违反B细胞的耐受性。该假设将在AIM 1中进行检验。总的来说，这些研究对机械起源O Systemi狼疮的红斑狼疮及其如何进行治疗具有重要意义。公共卫生相关性：我们对细胞内哪种信号通路在不同阶段的不同阶段最激活。该研究使用新型的遗传简化小鼠模型，旨在定义狼疮中不同细胞类型的精确分子贡献。这些研究还将确定在狼疮淋巴细胞中激活的2个特定分子是否对于疾病必不可少。使用这些新型遗传模型发现狼疮发病机理中的基本节点很可能为靶向关键信号淋巴结狼疮的更有效疗法铺平了道路。