INTEGRATIVE GENETIC APPROACHES TO GENE-AIR POLLUTION INTERACTIONS IN ASTHMA

哮喘中基因与空气污染相互作用的综合遗传方法

• 批准号: 8626197
• 负责人: FRANK D. GILLILAND
• 金额: $ 31.91万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626197
• 关键词: Address; Adverse effects; Affect; Air Pollutants; Air Pollution; Allergic inflammation; Area; Asthma; Basophils; Biological; Birth; Blood Circulation; Blood specimen; Bone Marrow; Cell Count; Cells; Cellular biology; Characteristics; Child health care; Cohort Studies; Collection; Complement; Data; Development; Diesel Exhaust; Environment; Environmental Exposure; Epidemiologic Studies; Epidemiology; Event; Exposure to; Flow Cytometry; Frequencies; Generations; Genes; Genetic; Genetic Variation; Goals; Health; Hematopoietic; Hematopoietic stem cells; Homeostasis; Human; Hybrids; Inbred Strains Mice; Inflammatory; Lead; Lung; Lung diseases; Maps; Mediating; Methodology; Methods; Modeling; Mothers; Mus; Newborn Infant; Orthologous Gene; Outcome; Parents; Peripheral; Phenotype; Physiology; Population; Predisposition; Principal Investigator; Protocols documentation; Recruitment Activity; Research; Research Personnel; Research Project Grants; Respiratory physiology; Statistical Methods; Stem cells; Structure; Synteny; Testing; Third Pregnancy Trimester; Umbilical Cord Blood; Variant; airway hyperresponsiveness; base; cohort; data sharing; eosinophil; experience; genetic analysis; genome wide association study; genome-wide; innovation; land use; lung repair; novel; particle; particle exposure; peripheral blood; pollutant; prenatal; progenitor; programs; public health relevance; response; response to injury; stem; trafficking

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.

项目摘要 许多流行病学研究表明，与交通有关的空气污染暴露对 哮喘和相关表型。最近出现的证据表明，改变造血 干/祖细胞（HSPC）稳态是一种潜在的重要的生物学机制，介导了造血干/祖细胞的分化。 与交通有关的空气污染对哮喘的不利影响。例如，造血祖细胞（HPC） 在肺部炎症事件后被动员，这表明这些骨髓（BM）来源的细胞 直接促进肺对损伤的修复。嗜酸性粒细胞和嗜碱性粒细胞在肺中的积聚是 也是过敏性炎症的特征，并与嗜酸性粒细胞水平的变化直接相关， 外周循环中的嗜碱性祖细胞。遗传因素也可能调节这些效应， 尽管目前还缺乏这一概念的直接证据。我们的挑衅性初步调查结果支持这一点 概念，并证明循环HPC的频率响应柴油机排气颗粒（DEP）， 一种典型的交通相关污染物，在9种近交系小鼠中变化约8倍，与 气道高反应性（AHR）。根据这些意见和目前正在采取的综合办法， 用于研究哮喘中的基因-环境（GxE）相互作用，我们组装了一个经验丰富的 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体内平衡和哮喘。作为ViCTER提案的一部分，该小组将 领导三个合作研究项目，旨在1）确定DEP对 一组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来确定HSPC和哮喘相关的GxE相关性 小鼠和人类的表型;以及3）确定遗传因素和交通相关空气的影响 产前发育期间的污染暴露对人脐带血样本中HSPC亚型的影响。 这些协调的活动涉及特征良好的人类群体，新的 与正在进行的研究相同的小鼠中的免疫表型数据，重新收集人HSPC数据，以及 应用新的统计方法，克服目前分析方法的局限性。的 这些努力的结果可能会对我们理解GxE在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， 流行病学和呼吸系统疾病的翻译影响。总体而言，拟议的研究 以有效的方式扩大和补充目前项目的范围，并将产生协同效应。 一个研究计划，由一组具有必要专业知识的研究人员组成，以成功实现目标 的拟议研究。