GENETIC MECHANISM OF OZONE INDUCED INFLAMMATION

背景：基于人群和流行病学的研究表明 在接触促炎氧化剂之间存在显著的相关性 污染区(O_3)与哮喘加重、肺功能 缺陷，以及儿童的缺课。因为它的影响 接触氧化剂可能会对儿童和成年人的健康产生影响， 识别影响的内在(宿主)因素 对空气污染物的易感性仍然是一个重要的问题。这个 作为宿主因素的遗传背景的潜在贡献 人们强烈建议人们对氧化性空气污染物的易感性，但 基因控制的性质仍不清楚。 总体目标。利用位置克隆和育种技术 确定决定差异易感性的一个或多个基因 对臭氧诱导的近交系小鼠肺部炎症和损伤的影响 并在人类基因组中寻找同源基因。 具体目标。我们设计了四个具体目标。在目标1中，我们 将生成对臭氧敏感性的高分辨率连锁图谱 诱导呼吸道炎症/上皮损伤。在目标2中，我们将 构建高分辨率的小鼠区域远程物理地图 17号和11号染色体携带臭氧易感基因。我们将利用 寻找同源人类的比较图谱方法 易感基因座。在目标3中，我们将培育同源品系的小鼠 包含赋予差异易感性的基因组区域 对炎症反应/上皮损伤的影响。最后，在目标4中，我们将 表征肺对In-03耐药的反应动力学 易感同基因小鼠品系通过以下途径评价其作用机制 其中磁化率基因调控差异磁化率。 关联性。这项建议采用了多学科的方法，将 提供对基因机制的独特见解，这些机制决定了 对臭氧引起的炎症的不同敏感性。因为在那里 是紧密连锁的同源性和保守的同源性的小鼠和 人类基因组，识别控制疾病易感性的基因 该模型中的O_3可以提供表征人类个体的手段 面临氧化剂暴露风险的人群，以及潜在的新 干预策略。

BACKGROUND: Population-based and epidemiological studies have demonstrated significant associations between exposures to the pro-inflammatory oxidant pollutant zone (O3) and exacerbation of asthma, pulmonary function deficits, and school absenteeism in children. Because of the impact that oxidant exposures may have on the health of children and adults, identification of the intrinsic (host) factors that influence susceptibility to airborne pollutants remains an important issue. The potential contribution of genetic background as a host factor for susceptibility to oxidant air pollutants has been strongly suggested but the nature of the genetic control is still unclear. OVERALL OBJECTIVE. To utilize positional cloning and breeding techniques to identify the gene or genes that determine differential susceptibility to O3-induced pulmonary inflammation and injury in inbred strains of mice and search for homologues in the human genome. SPECIFIC OBJECTIVES. We have designed four specific aims. In Aim 1, we will generate high-resolution linkage maps for susceptibility to O3- induced airways inflammation/epithelial injury. In Aim 2, we will construct high-resolution long-range physical maps of the regions of mouse chromosomes 17 and 11 carrying O3 susceptibility loci. We will utilize comparative mapping approaches to search for homologous human susceptibility loci. In Aim 3, we will develop congenic strains of mice that contain the genomic regions that confer differential susceptibility to inflammatory response/epithelial injury. Finally, in Aim 4 we will characterize the kinetics of lung response to in 03-resistant and - susceptible congenic mouse strains to evaluate the mechanisms through which the susceptibility locus modulates differential susceptibility. RELEVANCE. This proposal utilizes a multi-disciplinary approach that will provide unique insight into the genetic mechanisms that determine differential susceptibility to O3-induced inflammation. Inasmuch as there is close linkage homology and conserved synteny between the mouse and human genomes, the identification of genes that control susceptibility to O3 in this model may provide a means to characterize individuals in human populations who are at risk to oxidant exposures, and potential novel strategies for intervention.