INTEGRATIVE GENETIC APPROACHES TO GENE-AIR POLLUTION INTERACTIONS IN ASTHMA

项目总结 许多流行病学研究表明，与交通相关的空气污染暴露对 哮喘及相关表型。最近出现的证据表明，改变的造血功能 干细胞/祖细胞(HSPC)的稳态是一种潜在的重要的生物学机制。 与交通相关的空气污染对哮喘的不利影响。例如，造血祖细胞(HPC) 在肺部发生炎症事件后被动员，表明这些骨髓(BM)来源的细胞 直接促进肺损伤后的修复。嗜酸性粒细胞和嗜碱性粒细胞在肺内的聚集 也是过敏性炎症的特征，与嗜酸性粒细胞和 外周循环中的嗜碱性粒细胞前体细胞。也可能是遗传因素调节了这些效应， 尽管目前缺乏对这一观点的直接证据。我们具有挑衅性的初步发现支持这一点 概念并证明了柴油机尾气颗粒物(DEP)对循环HPC的响应频率， 一种与交通相关的模型污染物，在9个近交系小鼠中变化~8倍，并与 呼吸道高反应(AHR)。基于这些观察和目前的综合方法 用来研究哮喘的基因-环境(GxE)相互作用，我们汇集了一个经验丰富的 跨学科研究团队，全面调查遗传因素之间的相互关系， 与交通相关的空气污染、HSPC动态平衡和哮喘。作为维克特提案的一部分，该组织将 领导三个合作研究项目，旨在1)确定DEP对以下方面的影响 近交系小鼠骨髓和外周血中HSPC亚型及其与AHR的关系； 2)应用创新的统计遗传学方法确定GxE与HSPC和哮喘相关的关联 老鼠和人类的表型；以及3)确定遗传因素和交通相关空气的影响 胎儿发育过程中污染暴露对人脐血HSPC亚型的影响 这些协调的活动涉及到具有良好特征的人类队列，新的 与正在进行的研究相同的小鼠的免疫表型数据，人类HSPC数据的从头收集，以及 应用新的统计方法，克服当前分析方法的局限性。这个 这些努力的结果可能会对我们理解GxE在哮喘和哮喘中的作用产生重大影响 揭示涉及HSPC生物学的潜在生物学机制，可能具有重要的生物学、 对呼吸系统疾病的流行病学和翻译影响。总而言之，拟议的研究 以高效的方式扩大和补充当前项目的范围，并将产生协同效应 在具有成功实现目标所需专业知识的调查团队中进行研究计划 建议进行的研究。

PROJECT SUMMARY Numerous epidemiological studies have shown the adverse effects of traffic-related air pollution exposure on asthma and related phenotypes. Recent emerging evidence suggests that altered hematopoietic stem/progenitor cell (HSPC) homeostasis is one potentially important biological mechanism mediating the adverse effects of traffic-related air pollution on asthma. For example, hematopoietic progenitor cells (HPCs) are mobilized following inflammatory events in the lung, suggesting that these bone marrow (BM)-derived cells directly contribute to lung repair in response to injury. Accumulation of eosinophils and basophils in the lung is also a characteristic of allergic inflammation and is directly related to changes in the levels of eosinophil and basophil progenitors in the peripheral circulation. It is also likely that genetic factors modulate these effects, although direct evidence for this notion is currently lacking. Our provocative preliminary findings support this concept and demonstrate that the frequency of circulating HPCs in response to diesel exhaust particles (DEP), a model traffic-related pollutant, varies ~8-fold among 9 inbred mouse strains and is inversely correlated with airway hyperreactivity (AHR). Based on these observations and the integrative approaches currently being used to investigate gene-environment (GxE) interactions in asthma, we have assembled a highly experienced trandisciplinary research team to comprehensively investigate the interrelationships between genetic factors, traffic-related air pollution, HSPC homeostasis, and asthma. As part of this ViCTER proposal, this group will lead three collaborative research projects aimed at 1) determining the effects of DEP on the repertoire of HSPC subtypes in BM and peripheral blood and their relationships to AHR in a panel of inbred mouse strains; 2) applying innovative statistical genetics methods to identify GxE association for HSPCs and asthma-related phenotypes in both mice and humans; and 3) determining the effects of genetic factors and traffic-related air pollution exposure during prenatal development on HSPC subtypes in human umbilical cord blood samples. These coordinated activities involve well-characterized human cohorts, the generation of new immunophenotypic data in the same mice as in ongoing studies, de novo collection of human HSPC data, and the application of novel statistical methodology that overcome limitations of current analytical approaches. The results of these efforts could have a significant impact on our understanding of GxE effects in asthma and reveal underlying biological mechanisms involving HSPC biology that may have important biological, epidemiological, and translational implications for respiratory diseases. Taken together, the proposed studies expand and complement the scope of current projects in an efficient manner and will generate a synergistic research program among a team of investigators with the requisite expertise to successfully achieve the goals of the proposed studies.