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