Identification of Mouse Airway Hyperresponsiveness Genes

小鼠气道高反应性基因的鉴定

• 批准号: 7312454
• 负责人: DAVID R. BEIER
• 金额: $ 44万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7312454
• 关键词: asthma; atopy; biotechnology; bronchomotion; gene expression; genetic markers; genetic regulation; genetic susceptibility; genotype; laboratory mouse; linkage mapping; mast cell; phenotype; quantitative trait loci; respiratory airflow disorder; respiratory hypersensitivity; single nucleotide polymorphism

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.

气道高反应性（AHR）是哮喘的组成部分，哮喘和AHR的复杂遗传使很难找到这些重要问题的遗传病因。在不太异质的遗传系统中，比人口较少的分析对于鉴定因果基因座可能有用。我们和其他人在小鼠中使用定量性状基因座（QTL）进行了尝试，该分析为NATVE AHR提供了出色的模型，但是这些研究的结果并不一致。作为该程序的一部分，我们使用了一种非常不同的方法来解决此问题。我们创建了表型选择的重组先天小鼠，以识别与增加Natve AHR相关的基因座。第七代高反应性小鼠在染色体2、6和10上保留了A/J基因座。令人惊讶的是，对未选择的N8后代的分析表明，幼稚的AHR表型并未与任何单独的基因座显着相关，但与该位点相互作用高度显着相关，与这些染色体的相互作用相互作用。同样，作为程序的一部分，我们生成了肥大细胞遗传耗尽的A/J小鼠。这些小鼠没有表现出天真的AHR，表明该性状是由肥大细胞介导的。 鉴定包含与AHR相关的基因座的基因组区域 证明这种特征需要它们的相互作用，并且观察到表达疾病表型需要肥大细胞对人类哮喘的遗传病因的解剖具有重要意义。 有趣的是，通过遗传分析与人类疾病相关的蛋白酶ADAM33在保留的A/J区域内。模型系统的一个优点是它们可以促进功能分析，我们建议使用单倍型分析和转基因检查ADAM33的作用。我们还建议进一步研究肥大细胞在介导通过相互骨髓移植和产卵中观察到的A/J小鼠中天真的AHR中的作用。最后，我们将继续缩小因果基因座所在的遗传间隔，目的是最终使用位置克隆策略来识别基因。