Identification of Mouse Airway Hyperresponsiveness Genes

气道高反应性（AHR）是哮喘的一个组成部分，哮喘和AHR的复杂遗传使得很难找到这些重要问题的遗传病因。在异质性较低的遗传系统中进行分析，可能对确定因果位点有用。我们和其他人已经尝试在小鼠中使用数量性状位点（QTL）分析，这为naTve AHR提供了一个很好的模型，但这些研究的结果并不一致。作为该计划的一部分，我们采用了一种非常不同的方法来解决这个问题。我们创建了表型选择的重组基因小鼠，以确定与native AHR增加相关的位点。第七代高反应小鼠在第2、6和10号染色体上保留了A/J位点。令人惊讶的是，对未选择的N8后代的分析表明，原始AHR表型与任何单个位点都没有显著相关性，但与染色体2和6上的位点的相互作用高度显著相关。这些发现在对经济小鼠的独立分析中得到证实。此外，作为项目的一部分，我们培育了肥大细胞基因缺失的A/J小鼠。这些小鼠没有表现出幼稚AHR，表明这种特性是由肥大细胞介导的。包含AHR致病位点的基因组区域的鉴定

Airway hyperresponsiveness (AHR) is a component of asthma, and the complex inheritance of both asthma and AHR have made it difficult to find the genetic etiology of these important problems. Analysis in a less heterogeneous genetic system than the human population could be useful for identifying causal loci. We and others have attempted this using quantitative trait locus (QTL) analysis in the mouse, which provides an excellent model for naTve AHR, but the results of these studies have been inconsistent. As part of this Program, we have used a very different approach to address this. We created phenotypically selected recombinant congenic mice to identify loci associated with increased naTve AHR. The seventh generation hyperresponsive mice retained A/J loci on chromosomes 2, 6, and 10. Surprisingly, analysis of unselected N8 progeny demonstrated that the naive AHR phenotype was not significantly associated with any of the loci individually, but was highly significantly associated with an interaction of loci on chromosomes 2 and 6. These findings were confirmed in an independent analysis of consomic mice. Also, as part of the Program, we generated A/J mice that are genetically depleted of mast cells. These mice do not show naive AHR, demonstrating that this trait is mediated by mast cells. The identification of genomic regions containing loci causally associated with AHR, the demonstration that this trait requires their interaction, and the observation that mast cells are required for expression of the disease phenotype has important implications for the dissection of the genetic etiology of asthma in humans. Of interest is that the protease ADAM33, which has been associated with the human disease by genetic analysis, is within the retained A/J region. An advantage of model systems is that they can facilitate functional analysis, and we propose to examine the role of ADAM33 using haplotype analysis and transgenesis. We also propose to further examine the role of mast cells in mediating the naive AHR observed in A/J mice by reciprocal bone marrow transplant and adoptive transfer. Lastly, we will continue to narrow the genetic interval in which the causal loci reside, with the aim of ultimately identifying the genes using a positional cloning strategy.