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; 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由遗传学，环境触发器和随机事件的结合而产生的。 尽管环境/异种剂在触发自身免疫性中的作用尚不清楚 如果特发性和实验性诱导的疾病是通过常见的遗传，分子和细胞途径引起的。 遗传研究表明，特发性和异种生物诱导的全身自身免疫模型 共享共同的要求以及显着差异，例如炎症体的重要性和 类型I干扰素。缺乏遗传和表型标准以区分特发性和 环境/异生物诱导的全身性自身免疫性疾病是我们理解的关键障碍 通常，自身免疫性。事实证明，近交性实验室小鼠菌株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一种遗传统一的动物。但是， 普通实验室菌株中的受限遗传异质性主要源自两个原始 亚洲和欧洲的幻想老鼠限制了目前认为发挥作用的常见变体的多样性 在系统自身免疫等复杂疾病中的主要作用。我们建议协作十字架（CC） 小鼠面板更适合对复杂疾病中表型的范围进行建模，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跨大型，异质和 可重复的人群，并结合了来自不同大陆的三种野生小鼠的基因组。 因此，CC小鼠应变为建模环境/异种生物引起的自身免疫提供了强大的工具 在遗传异质的人群中。为了测试这一点，我们将检查CC菌株对结晶的响应 二氧化硅和HGCL2。之所以选择这两个代理，是因为HGCL2引起自身免疫的特征 （自身抗体，肾脏疾病），而不是人类和小鼠的明显疾病，而结晶二氧化硅会诱导 两者的全身性自身免疫性疾病。我们假设重组CC面板的遗传多样性 近交（RI）菌株将使我们能够表明暴露于HGCL2，二氧化硅会导致免疫的不同特征 介质，炎症，自身抗体和病理学解释了它们不同的疾病严重程度。 此外，我们认为使用CC RI菌株不仅会显着提高我们识别遗传的能力 基因座，但还确定特定的基因和分子途径，以区分HGCL2和二氧化硅诱导 彼此的全身自身免疫性疾病以及特发性全身自身免疫性。我们将解决 这三个目标。特定目标1：CC RI菌株中基线血清生物标志物的分析，特定目标2： CC RI小鼠中异种生物诱导的自身免疫性的诱导和分析，特定目标3：遗传学映射 CC RI小鼠中异生物诱导的自身免疫。这些研究的成功完成应导致 对异种生物诱导的全身自身免疫性的潜在遗传学和生物标志物有更深入的了解， 增强诊断能力，并确定潜在的治疗靶点。