The Diversity Outbred Mouse as a Model of Silica-induced Autoimmunity

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DESCRIPTION (provided by applicant): Inbred mouse strains have proven vital for biomedical research because the inbred genotype provides a genetically uniform animal for experimental purposes. However, the limited genetic heterogeneity can result in strain specific differences in phenotypic response when examining complex diseases such as environmentally- induced autoimmunity. Determining the full spectrum of immunological responses may therefore require testing of numerous inbred strains which can be both time consuming and costly. In this grant application the investigators propose that the Diversity Outbred (DO) mouse is better suited to model complex disease due to its extensive genetic and phenotypic variation. Unlike inbred mice, each DO mouse has a unique combination of alleles and this genetic variation is more evenly distributed across the genome. In addition, the increase in recombination events dramatically improves mapping of quantitative trait loci. The DO mouse thus provides a powerful new tool for genome-wide association studies and should provide a superior approach to model responses in genetically heterogeneous populations, including human populations, than inbred mice. To test this, the investigators will examine the response of the DO mouse to crystalline silica. They have chosen silica because even though there is considerable evidence that silica exposure is associated with autoimmunity in humans, an acceptable animal model does not exist. The investigators hypothesize that the genetic heterogeneity of DO mice will allow development of a range of immunological and pathological responses to silica, including autoimmunity. To test this hypothesis the investigators will undertake two distinct, yet overlapping, aims. In Aim 1 they will determine the reaction of DO mice to crystalline silica by characterizing the spectrum of immunological responses leading to autoimmunity. The parameters to be examined are based on human immunological responses to silica and will include the inflammatory response in the lung, proinflammatory cytokine production, activation of the adaptive immune response, autoantibodies and tissue pathology. In Aim 2 the investigators will identify quantitative trait loci (QTL) associated with the immunological parameters following exposure of DO mice to crystalline silica. These studies will use the Mega Mouse Universal Genotyping Array (MegaMUGA), a high-density genotyping array with special emphasis on markers in the DO mouse and founder strains, and analysis tools such as DOQTL, a QTL mapping software specifically developed to perform linkage and association mapping in DO mice.