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， 近交基因型提供了用于实验目的的遗传均一的动物。不过有 常见实验室菌株之间的遗传异质性有限，主要是由于起源于两个 原始的亚洲和欧洲花式老鼠。这大大减少了常见遗传变异的多样性 被认为对系统性自身免疫等复杂特征有重要贡献。我们建议 协作杂交（CC）重组近交（RI）组最适合于模拟表型范围， 复杂的疾病，因为它是唯一具有全基因组遗传变异的实验性哺乳动物资源 在一个大的、异质的和可重复的群体中随机化。值得注意的是，CC RI小组增加了 来自三个不同大陆的三种野生菌株的基因组，这些菌株在常见的近交系中不存在 菌株因此，CC菌株提供了一个强大的工具，以更遗传的方式模拟自身免疫。 比以前更多样化的面板。因此，我们假设，更大的遗传异质性 包括来自野生来源菌株的贡献，将允许开发广泛的 从表面健康到全身性自身免疫的免疫和病理特征。而且我们 这将适用于基因分型和数量性状基因座（QTL）分析的方式是不可能的 以前的方法。这得到了我们的初步研究的支持，该研究表明CC菌株表现出 不同水平的自发性抗核自身抗体（ANA）和炎症生物标志物， 被分为许多表型。此外，野生来源的菌株的存在有助于 ANA阳性定位于1号和17号染色体上的基因座。我们相信对这些人的调查 免疫介质、细胞炎症、自身抗体和病理学将导致 鉴定出比目前可用的更多样的自身免疫表型谱。另外我们 我认为，分析CC RI株中不同的自身免疫表型将增强我们的能力， 确定特定的基因和分子和细胞途径，区分进展中的步骤， 表观健康、亚临床炎症和/或自身免疫、全身性自身免疫疾病。我们 将从两个方面来解决这个问题。具体目的1：在CC RI菌株中产生全身性自身免疫，以及 具体目的2：CC RI小鼠中全身性自身免疫的遗传作图。 这些研究的成功完成应该会导致识别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，对遗传学的更好理解， 生物标志物和全身性自身免疫的发病机制，以及潜在治疗靶点的鉴定。

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.