Collaborative Cross Strains as Models of Systemic Autoimmunity

近亲繁殖的实验室小鼠品系已被证明对系统性自身免疫性疾病的研究至关重要，因为 近亲交配的基因为实验目的提供了一种基因一致的动物。然而，还有 常见实验室菌株之间的遗传异质性受到限制，主要是由于两个菌株的起源 原创的亚洲和欧洲花式老鼠。这大大降低了常见遗传变异的多样性。 被认为对系统自身免疫等复杂特征有重大贡献的基因。我们建议， 协作杂交(CC)重组近交系(RI)面板最适合对 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 在一个庞大的、异质的和可重复的种群中随机进行。值得注意的是，CC RI小组增加了 来自三个不同大陆的三个未在普通近交系中表现出来的野生菌株的基因组 菌株。因此，CC毒株提供了一个强大的工具来在更具遗传性的情况下模拟自身免疫 比以前更多样化的面板。因此我们假设，更大的遗传异质性 CC菌株，包括来自野生来源的菌株的贡献，将允许开发广泛的 从表面健康到全身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服从于基因分型和数量性状基因座(QTL)分析 与以前的方法相同。这一点得到了我们的初步研究的支持，这些研究表明CC菌株表现出 不同水平的自发抗核自身抗体(ANA)和炎性生物标记物，使它们 分成多个表型。此外，野生来源菌株的存在也导致了 ANA阳性与1号和17号染色体上基因座的定位。我们认为，对ANA阳性的研究 免疫介质、细胞炎症、自身抗体和病理在CC RI小组中将导致 鉴定比目前可用的更多样化的自身免疫表型谱。此外，我们 认为分析CC RI菌株之间不同的自身免疫表型将增强我们的能力 识别特定的基因以及分子和细胞通路，以区分进展中的步骤 表面健康，亚临床炎症和/或自身免疫，全身自身免疫性疾病。我们 将通过两个目标解决这一问题。具体目标1：CC RI株的系统自身免疫的发展，以及 特定目的2：CC RI小鼠系统自身免疫的遗传图谱。 这些研究的成功完成应该会导致发现新的小鼠品系来研究进展 从明显的健康到系统性疾病的自身免疫，对遗传学的更好理解， 生物标记物，系统性自身免疫的发病机制，以及潜在治疗靶点的确定。

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.