Aberrant DNA Repair and Lupus

异常 DNA 修复和狼疮

• 批准号: 10210397
• 负责人: Joann B. Sweasy
• 金额: $ 75.43万
• 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/10210397
• 关键词: Address; Affect; African; African American; American; Antinuclear Antibodies; Asian Americans; Asians; 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 Americans; Hispanics; 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; 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.

项目摘要/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， 是无药可救的。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 表现是异质的，女性患 SLE 的可能性是男性的九倍，而狼疮是 在亚洲人、西班牙人、美洲原住民和非洲人血统的人中比在 欧洲血统。狼疮是一种尚未得到充分研究的疾病。发现同卵双胞胎的一致性是 低至 25%，家族聚集性研究表明狼疮至少部分是由遗传引起的 倾向。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 修复会导致 小鼠模型中的狼疮。我们最初表明，小鼠 POLB 基因的突变会导致 由于 VDJ 重组缺陷和体细胞超突变而导致狼疮的发生。合作中 与 Lindsey Criswell 博士合作，我们现已鉴定出大量编码种系变异，这些变异富含 患有狼疮的人。在初步研究中，我们已经证明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 项目专注于提供有关狼疮发展的机制见解 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 暴露会影响狼疮的发展。我们认为之前的许多分析可能不够有力 因为所研究的个体的遗传倾向因素可能有所不同，并且遗传因素 在生物体对环境的反应中发挥着重要作用。我们应对这一挑战的方法 是构建DNA修复基因中编码遗传变异的小鼠模型，这些变异显着富集于 患有狼疮的人。接下来将描述这些疾病中出现的疾病病理学特征 小鼠在不存在和存在已知与狼疮发展相关的环境暴露的情况下。 然后，我们将采取结合遗传、分子和生化的方法来阐明潜在的机制 深入了解狼疮的发展。我们的项目具有揭示遗传和 狼疮发展的环境基础，并产生影响治疗的范式转变结果 这种毁灭性的疾病。