Gene-environment interactions in asthma in mice and humans

我们已经建立了尘螨诱发哮喘的小鼠模型，该模型概括了人类哮喘的主要特征，即呼吸道高反应性、炎症和粘液产生。为了确定介导这两种表型易感性的基因，我们正在进行一个大型数量性状基因座(QTL)定位项目，使用一个新建立的遗传多样性小鼠群体，称为协作杂交(CC)。CC系小鼠由普通品系(A/J、C57BL/6J、129/SvImJ、NOD/ShILtd J和Nzo/HILtd J)与野生品系(WSB/EIJ、PWK/PhJ和CAST/EIJ)杂交而成。CC的设计目的是捕捉近交系的最大遗传多样性，同时将种群结构的影响降至最低，从而克服了以往作图方法的许多局限性。到目前为止，我们已经对150多只小鼠进行了表型鉴定，并进行了三个值得注意的观察：(1)这些小鼠表现出令人难以置信的哮喘表型多样性，(2)基础肺功能与DerP1攻击后的肺功能密切相关，(3)DerP1引起的呼吸道炎症程度与肺功能受损无关。 在明年，我们计划完成所有CC菌株的表型鉴定，然后与北卡罗来纳大学和杰克逊实验室的同事合作绘制QTL图。一旦确定了QTL，我们计划通过已经进行的合作，测试人类同源物在基于人群的过敏性哮喘研究中的作用。

We have established a mouse model of dust mite-induced asthma that recapitulates the key features of human asthma, namely airway hyper-responsiveness, inflammation, and mucus production. In order to identify genes that mediate susceptibility to these two phenotypes, we are conducting a large quantitative trait locus (QTL) mapping project using a newly establishing population of genetically diverse mice known as the Collaborative Cross (CC). Mice from the CC are derived from an eight-way cross of common (A/J, C57BL/6J, 129/SvImJ, NOD/ShILtJ and NZO/HILtJ) and wild-derived (WSB/EiJ, PWK/PhJ and CAST/EiJ) inbred strains. The CC was designed to capture maximal genetic diversity of inbred strains and at the same time minimize the effects of population structure, thereby overcoming many of the limitations of previous mapping approaches. Thus far, we have phenotyped more than 150 mice and have made three notable observations: (1) these mice exhibit an incredible range of asthma phenotype diversity, (2) baseline lung function is strongly correlated with lung function after Derp1 challenge, and (3) the degree of airway inflammation caused by Derp1 does not correlate with impaired lung function. During the next year, we plan to finish phenotyping all CC strains, then map the QTLs in collaboration with colleagues at the University of North Carolina and the Jackson Laboratory. Once QTL have been identified, we plan to test the role of human homologs in population-based studies of allergic asthma through collaborations that are already underway.