Aberrant DNA Repair and Lupus

项目摘要/摘要： 100多万美国人患有系统性红斑狼疮，这是一种自身免疫性疾病，在美国 是无法治愈的。系统性红斑狼疮(SLE或狼疮)是一种慢性自身免疫性疾病。这种病 表现是异质性的，女性患系统性红斑狼疮的可能性是男性的九倍，而狼疮则是 在亚裔、西班牙裔、美洲原住民和非洲血统的人中明显比 欧洲血统。狼疮是一种研究严重不足的疾病。单合子双胞胎的一致性被发现是 低至25%的家族聚集性研究表明，狼疮至少部分是由遗传基因引起的 性情。该领域的大多数专家都认为基因与环境的相互作用对狼疮很重要。 发展。我们实验室最近的工作表明，异常的DNA修复导致了 狼疮是一种小鼠的疾病模型。我们最初在老鼠身上发现了POLB基因的突变 由于VDJ重组缺陷和体细胞过度突变而导致的狼疮的发生。在协作中 与林赛·克里斯韦尔博士一起，我们现在已经确定了大量编码生殖系变体，它们富含 狼疮患者。在初步研究中，我们已经证明了携带这些变体之一的小鼠 在错配修复途径中产生高水平的抗核抗体和狼疮相关肺 疾病。我们已经证明，这些小鼠的体细胞过度突变是不正常的，并导致产生 自身抗体。我们的River项目专注于为狼疮的发展提供机械性的见解 作为基因-环境相互作用的结果。该领域的一项挑战是了解环境如何 暴露会影响狼疮的发展。我们认为，以前的许多分析可能缺乏说服力。 因为所研究的个体的遗传易感因素可能不同，而遗传因素 在生物体对环境的反应中起着重要作用。我们应对这一挑战的方法 是构建编码DNA修复基因遗传变异的小鼠模型，这些变异显著富含 狼疮患者。接下来将描述在这些疾病中出现的疾病病理特征 缺乏和存在已知与狼疮发病有关的环境暴露的小鼠。 然后，我们将采用遗传、分子和生物化学相结合的方法来阐明潜在的机制。 对狼疮发展的洞察。我们的项目有很大的潜力来发现基因和 红斑狼疮发展的环境基础，并产生将影响治疗的范式转换结果 这种毁灭性的疾病。

Project Summary/Abstract: Over one million Americans suffer from Systemic Lupus Erythematosus, an autoimmune disease for which there is no cure. Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease. The disease presentation is heterogenous, women are nine times more likely to develop SLE than men, and lupus is significantly more prevalent in people of Asian, Hispanic, Native American, and African ancestry than people of European ancestry. Lupus is a significantly understudied disease. Monozygotic twin concordance is found to be as low as 25% and familial aggregation studies suggest that lupus results at least in part from genetic predisposition. Most experts in the field agree that gene-environment interactions are important for lupus development. Recent work from our laboratory suggests that aberrant DNA repair leads to the development of lupus in a mouse model of the disease. We originally showed that a mutation in the POLB gene in mice results in development of lupus as a result of defective VDJ recombination and somatic hypermutation. In collaboration with Dr. Lindsey Criswell we have now identified a large number of coding germline variants that are enriched in individuals with lupus. In preliminary research, we have demonstrated that mice harboring one of these variants within the mismatch repair pathway develop high levels of antinuclear antibodies and lupus-associated lung disease. We have shown that somatic hypermutation is abnormal in these mice and results in the production of autoantibodies. Our RIVER project is focused on providing mechanistic insights into the development of lupus as a result of gene-environment interactions. A challenge in the field is understanding how environmental exposures influence lupus development. We suggest that many previous analyses may be underpowered because the genetic predisposition factors of the individuals studied are likely to differ, and that genetic factors play a significant role in the response of the organism to the environment. Our approach to address this challenge is to construct mouse models of coding genetic variants in DNA repair genes that are significantly enriched in individuals with lupus. This will be followed by characterization of the disease pathologies emerging in these mice in the absence and presence of environmental exposures that are known to be linked to lupus development. We will then take a combined genetic, molecular, and biochemical approach to elucidate underlying mechanistic insights into the development of lupus. Our project has significant potential to uncover the genetic and environmental bases of lupus development and to yield paradigm-shifting results that will impact the treatment of this devastating disease.