Aberrant DNA Repair and Lupus

异常 DNA 修复和狼疮

• 批准号: 10381734
• 负责人: Joann B. Sweasy
• 金额: $ 76.37万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-06 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381734
• 关键词: Address; Affect; African American; African American population; African ancestry; American; Antinuclear Antibodies; Asian Americans; Asian population; Autoantibodies; Autoimmune Diseases; Biochemical; Code; Collaborations; DNA Repair; DNA Repair Gene; Development; Disease; Disease model; Environment; Environmental Exposure; European; Genetic; Genetic Code; Genetic Predisposition to Disease; Hispanic; Hispanic Americans; Immunoglobulin Somatic Hypermutation; Individual; Laboratories; Link; Lung diseases; Lupus; Mismatch Repair; Molecular; Monozygotic twins; Mus; Mutation; Native American Ancestry; Native Americans; Organism; POLB gene; Pathology; Pathway interactions; Persons; Play; Production; Research; Role; Systemic Lupus Erythematosus; Time; V(D)J Recombination; Variant; Woman; Work; base; chronic autoimmune disease; gene environment interaction; genetic variant; insight; men; mouse model; response

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.

项目概要/摘要： 超过一百万美国人患有系统性红斑狼疮，这是一种自身免疫性疾病， 无法治愈系统性红斑狼疮（SLE或狼疮）是一种慢性自身免疫性疾病。疾病 表现是异质性的，女性比男性更容易患SLE，并且狼疮是 在亚洲人、西班牙人、美洲原住民和非洲血统的人中， 欧洲血统。狼疮是一种研究严重不足的疾病。单卵双生子一致性被发现是 低至25%，家族聚集性研究表明，狼疮至少部分是遗传性的。 易感性该领域的大多数专家都认为基因-环境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 狼疮的小鼠模型。我们最初表明，小鼠POLB基因的突变导致 在狼疮的发展中作为缺陷VDJ重组和体细胞超突变的结果。合作 与Lindsey Criswell博士一起，我们现在已经确定了大量的编码生殖系变异，这些变异富含 狼疮患者在初步研究中，我们已经证明，携带这些变异之一的小鼠 在错配修复途径中产生高水平的抗核抗体和狼疮相关的肺 疾病我们已经证明，这些小鼠的体细胞超突变是异常的，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制性见解 是基因与环境相互作用的结果。该领域的一个挑战是了解环境如何 暴露影响狼疮的发展。我们认为，许多以前的分析可能是不够有力的 因为所研究的个体的遗传易感因素可能不同，并且遗传因素 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 是构建小鼠模型的编码遗传变异的DNA修复基因，显着丰富的， 狼疮患者这将是随后出现的疾病病理特征，在这些 小鼠在缺乏和存在已知与狼疮发展有关的环境暴露的情况下。 然后，我们将采取一个综合的遗传，分子和生物化学的方法来阐明潜在的机制， 对狼疮发展的深入了解我们的项目有很大的潜力来揭示基因和 狼疮发展的环境基础，并产生将影响治疗的范式转变结果， 这种毁灭性的疾病。