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学、环境诱因和随机事件共同作用的结果。 尽管环境/异源因子在触发自身免疫中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常见的遗传、分子和细胞途径引起的。 遗传学研究表明，特发性和异物诱导的系统性自身免疫动物模型 既有共同的要求，也有显著的差异，如炎症小结的重要性和 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/异物诱导的全身性自身免疫性疾病是我们理解 自体免疫力一般。近亲繁殖的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 因为近亲交配的基因为实验目的提供了一致的遗传基因。然而， 常见实验室菌株之间的限制性遗传异质性，主要来自两个原始菌株 亚洲和欧洲的花哨老鼠，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重要作用。我们建议协作十字(CC) 鼠标面板更适合于对复杂疾病的表型范围进行建模，因为它是唯一 具有全基因组遗传变异的哺乳动物资源，随机分布在一个巨大的、异质的和 它包含了来自不同大陆的三种野鼠品系的基因组。 因此，CC小鼠品系为模拟环境/异种生物诱导的自身免疫提供了有力的工具。 在一个遗传异质性的种群中。为了测试这一点，我们将检查CC菌株对晶状体的反应 二氧化硅和氯化汞。之所以选择这两种药物是因为HgCl2诱导了自身免疫的特征 (自身抗体，肾脏疾病)，但在人类和小鼠中不是显性疾病，而结晶二氧化硅导致 两者都有系统性自身免疫性疾病。我们假设重组人CC组的遗传多样性 近交系(RI)菌株将允许我们表明，暴露在HgCl2和二氧化硅中会导致不同的免疫模式 介质、炎症、自身抗体和病理，解释了它们不同的疾病严重程度。 此外，我们认为，使用CC RI菌株不仅将显著提高我们识别基因的能力 但也要确定区分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相互之间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：分析CC RI菌株的基线血清生物标记物； 异种生物诱导CC-RI小鼠自身免疫的诱导和分析及其特异性目标3：基因定位 异种生物诱导CC RI小鼠自身免疫的研究。成功完成这些研究应该会导致 更好地了解异种生物诱导的系统性自身免疫的潜在遗传学和生物标记物， 提高诊断能力，识别潜在的治疗靶点。