Genetic analysis of an asthma-related trait in mice

描述（由申请人提供）：气道高反应性（AHR）是哮喘的关键生理组成部分。虽然AHR在实验动物模型中可以通过抗原致敏而诱导，并且在致敏的人中可以通过抗原激发而增强，但在未致敏的个体中也很明显。这种复杂性状的遗传基础仍然难以捉摸。对表现出遗传性幼稚气道高反应性的小鼠进行分析，为确定其潜在的分子基础提供了一种方法。我们以前已经使用遗传作图来鉴定与AHR相关的数量性状位点（qtl）。我们还使用遗传和药理学分析来证明这种特性是由肥大细胞介导的。在这一建议中，我们计划继续使用最先进的遗传策略研究易患AHR的遗传位点，并评估肥大细胞在赋予菌株特异性AHR性状中的作用。

DESCRIPTION (provided by applicant): Airway hyperresponsiveness (AHR) is a key physiological component of asthma. While AHR is inducible in experimental animal models by sensitization to antigen and can be potentiated by antigen challenge in sensitized humans, it is also evident in non-sensitized (naive) individuals. The genetic basis of this complex trait has remained elusive. Analysis of mice that demonstrate heritable naive airway hyperresponsiveness provides a means to identify its underlying molecular basis. We have previously used genetic mapping to identify quantitative trait loci (QTLs) that confer AHR. We have also used genetic and pharmacological analysis to demonstrate that this trait is mediated by mast cells. In this proposal, we plan to continue our investigation of the heritable loci that predispose to AHR using state-of-the-art genetic strategies, and to assess the role of mast cells in conferring the strain-specific AHR trait. PUBLIC HEALTH RELEVANCE: Increased airway responsiveness to stimuli is a physiological component of human asthma. Genetic analysis of mice that demonstrate airway hyperresponsiveness as heritable trait provides a means to identify its underlying molecular basis, and potentially a method to treat it.