Collaborative Cross Strains as Models of Systemic Autoimmunity

协作交叉菌株作为系统性自身免疫模型

• 批准号: 10730346
• 负责人: Kenneth Michael Pollard
• 金额: $ 27.15万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-16 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730346
• 关键词: Alleles; Animal Experiments; Animal Model; Asian; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Biological Markers; Biological Response Modifiers; Characteristics; Chromosome Mapping; Chromosomes; Clinical; Complex; Computer software; Coupled; Data; Development; Disease; Environmental Exposure; European; Event; Exhibits; Genes; Genetic; Genetic Heterogeneity; Genetic Variation; Genetic study; Genome; Genotype; Goals; Health; Heterozygote; Human; Immunity; Immunologics; Inbred Mouse; Inbred Strain; Inbred Strains Mice; Inbreeding; Individual; Inflammation; Inflammatory; Influentials; Investigation; Laboratories; Laboratory mice; Link; Maps; Modeling; Molecular; Mouse Strains; Mus; Nuclear; Nuclear Antigens; Parents; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Population; Predisposition; Probability; Protocols documentation; Quantitative Trait Loci; Randomized; Recombinant Inbred Strain; Recombinants; Reproducibility; Research; Residual state; Resource Informatics; Resources; SNP array; Severities; Systemic disease; Testing; Variant; chemokine; clinically relevant; cytokine; disease diagnosis; disease phenotype; genetic association; genetic variant; genome-wide; genomic locus; human disease; improved; inflammatory marker; insight; lupus-like; mouse genome; phenotypic data; response; segregation; systemic autoimmune disease; systemic autoimmunity; therapeutic target; tool; trait

Inbred laboratory mouse strains have proven essential for research into systemic autoimmune diseases because the inbred genotype provides a genetically uniform animal for experimental purposes. However, there is restricted genetic heterogeneity among common laboratory strains primarily due to the origination from two original Asian and European fancy mice. This has significantly reduced the diversity of common genetic variants that are thought to contribute significantly to complex traits such as systemic autoimmunity. We propose that the Collaborative Cross (CC) Recombinant Inbred (RI) panel is the best suited to model the range of phenotypes in complex diseases because it is the only experimental mammalian resource with genome-wide genetic variation randomized across a large, heterogeneous and reproducible population. Significantly, the CC RI panel adds the genomes of three wild strains from three different continents that are not represented in the common inbred strains. Consequently, the CC strains provide a powerful tool to model autoimmunity in a much more genetically diverse panel than previously available. We therefore hypothesize that the much greater genetic heterogeneity of CC strains, including contributions from wild-derived strains, will allow development of a wide range of immunological and pathological features from apparent good health to systemic autoimmunity. Furthermore, we posit that this will be amenable to genotyping and quantitative trait locus (QTL) analysis in a way not possible with previous approaches. This is supported by our preliminary studies, which show that CC strains exhibit differing levels of spontaneous anti-nuclear autoantibodies (ANA) and inflammatory biomarkers, allowing them to be grouped into a number of phenotypes. Furthermore, the presence of wild-derived strains contributed to the mapping of ANA positivity to loci on chromosomes 1 and 17. We believe that investigation of the profiles of immune mediators, cellular inflammation, autoantibodies, and pathology in the CC RI panel will lead to the identification of a more diverse spectrum of autoimmune phenotypes than currently available. Additionally, we argue that analysis of the different autoimmune phenotypes among CC RI strains will enhance our ability to identify specific genes and molecular and cellular pathways that discriminate steps in the progression from apparent good health, to sub-clinical inflammation and/or autoimmunity, to systemic autoimmune disease. We will address this in two aims. Specific Aim 1: Development of systemic autoimmunity in CC RI strains, and Specific Aim 2: Genetic mapping of systemic autoimmunity in CC RI mice. Successful completion of these studies should result in identifying new strains of mice to study the progression of autoimmunity from apparent good health to systemic disease, a better understanding of the genetics, biomarkers, and pathogenesis of systemic autoimmunity, and identification of potential therapeutic targets.

近交实验室小鼠品系已被证明对于系统性自身免疫性疾病的研究至关重要，因为 近交基因型为实验目的提供了遗传均一的动物。然而，有 常见实验室菌株之间的遗传异质性有限，主要是由于源自两种菌株 原创亚洲和欧洲的精美鼠标。这显着减少了常见遗传变异的多样性 人们认为它们对系统性自身免疫等复杂特征有显着贡献。我们建议 协作杂交 (CC) 重组近交 (RI) 面板最适合对表型范围进行建模 复杂的疾病，因为它是唯一具有全基因组遗传变异的实验哺乳动物资源 在大量、异质且可重复的人群中随机进行。值得注意的是，CC RI 小组添加了 来自三个不同大陆的三种野生品系的基因组，这些品系在常见的近交系中没有体现 菌株。因此，CC 菌株提供了一个强大的工具，可以在更遗传的情况下模拟自身免疫。 比以前可用的面板更加多样化。因此，我们假设更大的遗传异质性 CC 菌株，包括来自野生菌株的贡献，将允许开发广泛的 从表面健康状况到系统性自身免疫的免疫学和病理学特征。此外，我们 假设这将以一种不可能的方式适应基因分型和数量性状位点（QTL）分析 与以前的方法。我们的初步研究支持了这一点，该研究表明 CC 菌株表现出 不同水平的自发抗核自身抗体（ANA）和炎症生物标志物，使它们 可分为多种表型。此外，野生菌株的存在也促进了 将 ANA 阳性映射到 1 号和 17 号染色体上的位点。我们相信对 CC RI 面板中的免疫介质、细胞炎症、自身抗体和病理学将导致 鉴定出比目前更多样化的自身免疫表型。此外，我们 认为对 CC RI 菌株之间不同自身免疫表型的分析将增强我们的能力 识别特定的基因以及分子和细胞途径，以区分进展中的步骤 表面健康状况良好、亚临床炎症和/或自身免疫、系统性自身免疫性疾病。我们 将通过两个目标来解决这个问题。具体目标 1：CC RI 菌株系统性自身免疫的发展，以及 具体目标 2：CC RI 小鼠全身自身免疫的基因图谱。 这些研究的成功完成应该会鉴定出新的小鼠品系来研究进展 从表面健康到全身性疾病的自身免疫，更好地了解遗传学， 生物标志物和系统性自身免疫的发病机制，以及潜在治疗靶点的识别。