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.

自身免疫被认为是遗传、环境触发因素和随机事件共同作用的结果。 尽管环境/外源物质在引发自身免疫方面的作用已得到充分证实，但尚不清楚 如果特发性和实验诱发的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，特发性和异生素诱导的系统性自身免疫动物模型 具有共同的要求和显着的差异，例如炎症小体和炎症小体的重要性 I型干扰素。缺乏区分特发性和特发性的遗传和表型标准 环境/外源性诱发的系统性自身免疫性疾病是我们理解的一个关键障碍 一般情况下的自身免疫。近交实验室小鼠品系已被证明对于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均一的动物。然而， 常见实验室菌株之间有限的遗传异质性主要来源于两种原始菌株 亚洲和欧洲的花哨小鼠限制了目前被认为发挥作用的常见变体的多样性 在系统性自身免疫等复杂疾病中发挥着重要作用。我们建议协作交叉（CC） 小鼠面板更适合模拟复杂疾病的表型范围，因为它是唯一的 具有全基因组遗传变异的哺乳动物资源，随机分布在大型、异质和 它包含了来自不同大陆的三种野生小鼠品系的基因组。 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 在遗传异质性人群中。为了测试这一点，我们将检查 CC 菌株对结晶的反应 二氧化硅和 HgCl2。选择这两种药物是因为 HgCl2 会诱发自身免疫特征 （自身抗体、肾脏疾病），但在人类和小鼠中不是明显的疾病，而结晶二氧化硅会诱发 两者都有系统性自身免疫性疾病。我们假设重组 CC 组的遗传多样性 近交 (RI) 菌株将使我们能够证明接触 HgCl2 和二氧化硅会导致不同的免疫特征 介质、炎症、自身抗体和病理学解释了它们不同程度的疾病严重程度。 此外，我们认为使用 CC RI 菌株不仅会显着提高我们识别遗传菌株的能力 基因座，还可以确定区分 HgCl2 和二氧化硅诱导的特定基因和分子途径 系统性自身免疫性疾病源于彼此以及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 菌株的基线血清生物标志物分析，具体目标 2： CC RI 小鼠中异生素诱导的自身免疫的诱导和分析，以及具体目标 3：遗传图谱 CC RI 小鼠中异生素诱导的自身免疫的研究。成功完成这些研究应该会产生 更好地了解外源性物质诱导的系统性自身免疫的潜在遗传学和生物标志物， 提高诊断能力，并确定潜在的治疗靶点。