Modeling xenobiotic-induced autoimmunity using Collaborative Cross strains.

使用协作交叉菌株模拟外源性诱导的自身免疫。

• 批准号: 9912022
• 负责人: Kenneth Michael Pollard
• 金额: $ 26.63万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912022
• 关键词: Address; Alleles; Animal Model; Animals; Asians; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological Markers; Biological Response Modifiers; Chromosome Mapping; Cluster Analysis; Complex; Computer software; Data; Development; Diagnostic; Disease; Environmental Exposure; European; Event; Exhibits; Exposure to; Genes; Genetic; Genetic Heterogeneity; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Genome; Genotype; Goals; Human; Inbred Mouse; Inbred Strains Mice; Inbreeding; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Interferon Type I; Kidney Diseases; Laboratories; Laboratory mice; Link; Mercuric chloride; Mercury; Modeling; Molecular; Mouse Strains; Mus; Pathogenesis; Pathology; Pathway interactions; Phenotype; Play; Population; Population Heterogeneity; Quantitative Trait Loci; Randomized; Recombinant Inbred Strain; Recombinants; Reproducibility; Research; Research Personnel; Resources; Role; SNP array; Serum; Severities; Severity of illness; Silicon Dioxide; Testing; Variant; Xenobiotics; crystallinity; disease phenotype; genetic association; genome-wide; genomic locus; human disease; improved; inflammatory marker; insight; novel; phenotypic data; response; systemic autoimmune disease; systemic autoimmunity; therapeutic target; tool

Autoimmunity is thought to result from a combination of genetics, environmental triggers, and stochastic events. Although the role of environmental/xenobiotic agents in triggering autoimmunity is well established, it is unclear if idiopathic and experimentally induced disease arise by common genetic, molecular and cellular pathways. Genetic studies have suggested that idiopathic and xenobiotic-induced animal models of systemic autoimmunity share common requirements as well as significant differences, such as the importance of the inflammasome and type I interferons. The lack of genetic and phenotypic criteria for discriminating between idiopathic and environmental/xenobiotic-induced systemic autoimmune disease is a critical barrier to our understanding of autoimmunity in general. Inbred laboratory mouse strains have proven vital for autoimmune disease research because the inbred genotype provides a genetically uniform animal for experimental purposes. However, the restricted genetic heterogeneity among the common laboratory strains that is primarily derived from two original Asian and European fancy mice, limits the diversity of common variants that are currently thought to play the major role in complex diseases such as systemic autoimmunity. We propose that the Collaborative Cross (CC) mouse panel is better suited to model the range of phenotypes in complex disease because it is the only mammalian resource with genome-wide genetic variation randomized across a large, heterogeneous and reproducible population and it incorporates the genomes of three strains of wild mice from different continents. Consequently, CC mice strains provide a powerful tool to model environmental/xenobiotic-induced autoimmunity in a genetically heterogeneous population. To test this, we will examine the response of CC strains to crystalline silica and HgCl2. These two agents have been chosen because HgCl2 induces features of autoimmunity (autoantibodies, kidney disease), but not overt disease in humans and mice, while crystalline silica induces systemic autoimmune disease in both. We hypothesize that the genetic diversity of the CC panel of recombinant inbred (RI) strains will allow us to show that exposure to HgCl2 and silica leads to different profiles of immune mediators, inflammation, autoantibodies, and pathology which explain their disparate levels of disease severity. Additionally, we argue that use of the CC RI strains will not only significantly improve our ability to identify genetic loci, but to also determine specific genes and molecular pathways that discriminate HgCl2- and silica-induced systemic autoimmune disease from each other as well as from idiopathic systemic autoimmunity. We will address this in three aims. Specific aim 1: Analysis of baseline serum biomarkers in CC RI strains, Specific Aim 2: Induction and analysis of xenobiotic-induced autoimmunity in CC RI mice, and Specific Aim 3: Genetic mapping of xenobiotic-induced autoimmunity in CC RI mice. Successful completion of these studies should result in a greater understanding of the underlying genetics and biomarkers of xenobiotic-induced systemic autoimmunity, enhancing diagnostic capability, and identification of potential therapeutic targets.

自身免疫性被认为是遗传、环境触发和随机事件的综合结果。 虽然环境/外源性物质在触发自身免疫中的作用已经得到了很好的证实，但目前还不清楚 如果自发性和实验诱导疾病是由共同的遗传、分子和细胞途径引起的， 遗传学研究表明，特发性和外源性诱导的全身性自身免疫动物模型 有共同的要求，也有显著的差异，如炎性小体的重要性， I型干扰素缺乏遗传和表型标准来区分特发性和 环境/外源性诱导的系统性自身免疫性疾病是我们理解 自身免疫近交实验室小鼠品系已被证明对自身免疫性疾病研究至关重要 因为近交基因型为实验目的提供了遗传上一致的动物。但 常见实验室菌株之间的有限遗传异质性主要来自两种原始菌株， 亚洲和欧洲的奇特老鼠限制了目前被认为发挥作用的常见变种的多样性 在复杂疾病中发挥重要作用，如系统性自身免疫。我们建议合作十字架（CC） 小鼠组更适合于模拟复杂疾病的表型范围，因为它是唯一的 哺乳动物资源与全基因组遗传变异随机在一个大的，异质的， 它是一个可重复的种群，它包含了来自不同大陆的三种野生小鼠的基因组。 因此，CC小鼠品系提供了一个强大的工具来模拟环境/外源性诱导的自身免疫 在一个基因异质的群体中。为了验证这一点，我们将检查CC菌株对晶体的反应， 二氧化硅和HgCl 2。之所以选择这两种药物，是因为HgCl 2可诱导自身免疫的特征 （自身抗体，肾脏疾病），但在人类和小鼠中没有明显的疾病，而结晶二氧化硅诱导 全身性自身免疫性疾病我们假设CC组的遗传多样性是重组 近交系（RI）菌株将使我们能够表明，暴露于HgCl 2和二氧化硅导致不同的免疫谱， 介质、炎症、自身抗体和病理学，这些因素解释了它们不同的疾病严重程度。 此外，我们认为，使用CC RI菌株不仅可以显着提高我们识别遗传物质的能力， 基因座，但也确定特定的基因和分子途径，区分氯化汞和二氧化硅诱导 系统性自身免疫性疾病相互之间以及来自特发性系统性自身免疫性疾病。我们将解决 这有三个目标。具体目标1：CC RI菌株中基线血清生物标志物的分析，具体目标2： CC RI小鼠中外源性诱导的自身免疫的诱导和分析，以及特定目标3：遗传作图 CC RI小鼠中外源性诱导的自身免疫性。成功完成这些研究应导致 对外源性诱导的全身性自身免疫的潜在遗传学和生物标志物有了更深入的了解， 增强诊断能力和鉴定潜在的治疗靶点。