Gene-Environment Interactions with Ozone in Experimental Asthma

 描述（由申请人提供）：暴露于空气污染与不良健康结果相关，预先存在心血管或呼吸系统疾病的人更容易受到影响。特别是，暴露于臭氧与哮喘恶化有关。还有一些研究表明，暴露于臭氧与哮喘的发展有关，尽管这些发现并不总是一致的。基因-环境相互作用（GxE）已被提出来解释臭氧与哮喘之间的关联在研究中的不一致性。研究人员提出，通过使用无偏见的全基因组方法在臭氧诱导的过敏性气道疾病（AAD）小鼠模型中识别这些GxE，他们可以深入了解臭氧影响肺部和免疫反应的机制。为了识别这些GxE，研究人员将利用一种新的小鼠遗传资源，即协作杂交（CC）。CC由一组重组自交系组成，这些自交系来自使用不同近交系的八向杂交，并为研究GxE和鉴定潜在的分子过程提供了理想的功能。基于先前的研究表明，臭氧使免疫系统向易过敏表型启动，研究人员设计了一项研究，其中小鼠首先暴露于臭氧（或过滤空气），然后通过气道进行屋尘螨（HDM）过敏原致敏和挑战（臭氧-HDM）。在目标1中，研究人员将描述100个CC品系中AAD表型对臭氧-HDM反应的群体水平变化和遗传力。根据这种分布，他们将确定对臭氧-HDM反应极端（高和低）的菌株。这些菌株将用于目标2，以测试单独对臭氧的反应（嗜中性粒细胞和气道高反应性）是否可预测对臭氧-HDM的反应，以及臭氧对几种免疫参数（巨噬细胞、CD 4 + T细胞和树突细胞数量和活化状态）的已知影响是否与对臭氧-HDM的反应相关。在目标3中，研究人员将使用全基因组方法确定臭氧对HDM反应的新遗传和基因组预测因子。具体而言，他们将使用RNA测序测量肺基因表达，并确定数量性状位点（QTL）和基因表达QTL（eQTL）。最后，通过合并QTL和eQTL数据，研究人员将使用先进的统计建模和生物信息学方法确定QTL的候选基因。总之，这项拨款申请利用创新而可行的方法来确定介导臭氧对随后对过敏原反应的影响的基因和途径，其结果将为研究臭氧对健康的影响提供新的途径。 臭氧

 DESCRIPTION (provided by applicant): Exposure to air pollution is associated with adverse health outcomes and people with pre- existing cardiovascular or respiratory disease are more susceptible. In particular, exposure to ozone is associated with exacerbations of asthma. There is also evidence from several studies that exposure to ozone is associated with the development of asthma, though these findings are not always consistent. Gene-environment interactions (GxE) have been proposed as an explanation for the inconsistency of the ozone -to-asthma association across studies. The investigators submit that by identifying these GxE in a mouse model of ozone-induced allergic airway disease (AAD) using an unbiased, genome-wide approach they can gain insight into the mechanisms by which ozone affects pulmonary and immune responses in the lung. To identify these GxE, the investigators will leverage a new mouse genetics resource, the Collaborative Cross (CC). The CC consists of a panel of recombinant inbred lines derived from eight-way crosses using a diverse set of inbred strains and provides ideal features for studying GxE and identifying the underlying molecular processes. Based on prior studies showing that ozone primes the immune system towards an allergy-prone phenotype, the investigators have designed a study in which mice are first exposed to ozone (or filtered air), and then are subjected to house dust mite (HDM) allergen sensitization and challenge (ozone-to-HDM) through the airway. In Aim 1, the investigators will characterize population level variation and heritability of AAD phenotypes in response to ozone-to-HDM among 100 CC lines. Based on this distribution, they will identify strains that have extreme responses (high and low) to ozone-to-HDM. These strains will be used in Aim 2 to test whether responses to ozone alone (neutrophilia and airway hyper-responsiveness) predict response to ozone-to-HDM and whether known effects of ozone on several immune parameters (macrophage, CD4+ T-cell, and dendritic cell number and activation status) are correlated with response to ozone-to-HDM. In Aim 3, the investigators will identify novel genetic and genomic predictors of response to ozone-to-HDM using genome- wide approaches. Specifically, they will measure lung gene expression using RNA-sequencing, and identify quantitative trait locus (QTL) and gene expression QTL (eQTL). Finally, by merging the QTL and eQTL data, the investigators will identify candidate genes for QTL using advanced statistical modeling and bioinformatic approaches. In summary, this grant application utilizes innovative and yet feasible approaches to identify genes and pathways that mediate the effect of ozone on subsequent response to allergen, and the results will offer new avenues of research into the health effects of ozone.