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

描述（由申请人提供）：近亲繁殖的小鼠品系已被证明对生物医学研究至关重要，因为近亲繁殖的基因型为实验目的提供了基因一致的动物。然而，当检测诸如环境诱导的自身免疫等复杂疾病时，有限的遗传异质性可能导致菌株特异性表型反应的差异。因此，确定免疫反应的全谱可能需要对许多近交菌株进行检测，这既耗时又昂贵。在这项拨款申请中，研究人员提出，由于其广泛的遗传和表型变异，多样性近亲繁殖（DO）小鼠更适合模拟复杂疾病。与近亲繁殖的小鼠不同，每只DO小鼠都有独特的等位基因组合，这种遗传变异在整个基因组中分布得更均匀。此外，重组事件的增加显著提高了数量性状位点的定位。因此，DO小鼠为全基因组关联研究提供了一个强大的新工具，并且应该提供比近亲繁殖小鼠更优越的方法来模拟遗传异质性群体（包括人类群体）的反应。为了验证这一点，研究人员将检查DO小鼠对结晶二氧化硅的反应。他们之所以选择二氧化硅，是因为尽管有大量证据表明二氧化硅暴露与人类自身免疫有关，但目前还没有可接受的动物模型。研究人员假设，DO小鼠的遗传异质性将允许对二氧化硅产生一系列免疫和病理反应，包括自身免疫。为了验证这一假设，研究人员将承担两个截然不同但又相互重叠的目标。在目标1中，他们将通过表征导致自身免疫的免疫反应谱来确定DO小鼠对结晶二氧化硅的反应。要检查的参数是基于人体对二氧化硅的免疫反应，包括肺部的炎症反应、促炎细胞因子的产生、适应性免疫反应的激活、自身抗体和组织病理学。在目标2中，研究人员将确定DO小鼠暴露于结晶二氧化硅后与免疫参数相关的数量性状位点（QTL）。这些研究将使用Mega Mouse Universal gentyping Array (MegaMUGA)，这是一种高密度基因分型阵列，特别强调DO小鼠和创始菌株的标记，以及DOQTL等分析工具，这是一种专门为DO小鼠进行连锁和关联定位而开发的QTL定位软件。

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.