GENETIC MECHANISM OF OZONE INDUCED INFLAMMATION

背景：基于人群和流行病学的研究表明， 暴露于促炎性氧化剂 污染带（O3）与哮喘发作、肺功能 赤字和儿童缺课。因为它的影响， 氧化剂暴露可能会对儿童和成人的健康产生影响， 确定影响的内在（宿主）因素 对空气传播的污染物的敏感性仍然是一个重要的问题。的 遗传背景作为宿主因素的潜在贡献 强烈建议对氧化剂空气污染物敏感， 基因控制的性质仍不清楚。 总体目标。利用定位克隆和育种技术 来鉴定决定不同易感性的基因 对O3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。 特定的替代品。我们制定了四个具体目标。目标1： 将产生高分辨率的连锁图谱， 诱导气道炎症/上皮损伤。在目标2中，我们 构建小鼠区域的高分辨率远程物理地图， 17号和11号染色体携带O3易感基因。我们将利用 比较作图法寻找同源人类 易感基因座在目标3中，我们将开发同类小鼠品系 这些基因组区域赋予不同的易感性 炎症反应/上皮损伤。最后，在目标4中， 表征肺对IN 03抗性和- 敏感的同类小鼠品系，以评估机制， 其中磁化率位点调节微分磁化率。 本案无关本提案采用多学科方法， 提供了独特的洞察力的遗传机制， 对O3诱导的炎症的不同易感性。因为 是小鼠和小鼠之间的紧密连锁同源性和保守的同线性， 人类基因组，确定控制易感性的基因， 该模型中的O3可以提供一种表征人类中个体的方法。 有氧化剂暴露风险的人群，以及潜在的新型 干预战略。

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.