Investigating gene x environment interaction using human exposures to O3 & LPS

描述（由申请人提供）：这项 NIEHS 挑战拨款是为了响应挑战主题 04-ES-102：使用受控人类暴露研究基因 x 环境相互作用。正如 RFA 中所述，“仔细控制人类受试者对低水平环境毒物（例如环境颗粒物、臭氧或柴油机尾气）的暴露，为帮助加强动物研究和基于人群的研究提供了机会，以更好地了解遗传学和暴露 (GxE) 之间的相互作用。为了解决这个主题，我们将采用两种经批准的暴露方案来获取个体对 0.4 ppm 臭氧持续 2 小时以及吸入 20,000 单位臭氧的反应表型。我们将通过招募志愿者加入臭氧协议，然后邀请完成臭氧研究的人员进行内毒素挑战来实现这一目标。臭氧是一种常见的污染物，而内毒素是颗粒物和生物气溶胶的主要成分。我们将检查的反应表型包括肺功能、气道炎症、气道和循环单核细胞、巨噬细胞和树突状细胞的免疫表型、气道和循环吞噬细胞功能。招募最初将集中于无效和充足的谷胱甘肽-S-转移酶 M1 (GSTM1) 基因型，以及烟酰胺腺嘌呤二核苷酸（磷酸）还原酶 (NQO1) 的无效和充足和单核苷酸多态性 (SNP)，以及由此产生的其他常见单核苷酸多态性。感兴趣的 (SNP) 存在于 NF-E2、相关因子 2 (NRF2)、GSTP1、GSTT1、谷胱甘肽过氧化物酶 (GPX1)、血红素加氧酶-1 (HO-1) 和超氧化物酶歧化酶 2 (SOD2)、CD14 基因启动子、TLR2、TLR4；IL-1、IL-1R 和 TNF 基因启动子中，而招募集中在 GSTM1。和 NQO1，其他基因的等位基因频率足够高，也将使用从气道和循环细胞中回收的 mRNA 进行基因表达谱评估，以确定调节对臭氧和 LPS 反应的新候选基因。 公共卫生相关性：从本研究中获得的知识可用于通过制定个人缓解策略和政策制定来减轻环境污染物对肺病和心血管疾病患者的影响。 《清洁空气法》要求国家环境空气质量标准保护弱势群体，包括那些从基因上定义脆弱性的群体。最后，这些研究还将进一步加深我们对人类常见病症病理生理学的理解。

DESCRIPTION (provided by applicant): This NIEHS challenge grant is written in response to challenge topic 04-ES-102: Investigating gene x environment interaction using controlled human exposures. As stated in the RFA, "Carefully controlled exposures of human subjects to low levels of environmental toxicants, such as ambient particulate matter, ozone, or diesel exhaust, provide an opportunity to help augment animal studies and population-based studies to better understand the interaction of genetics and exposure (GxE). To address this topic, we will employ two approved exposure protocols to access response phenotypes of individuals to 0.4 ppm ozone for 2 hours, and inhalation of a 20,000 units of endotoxin. We will achieve this by recruiting volunteers into the ozone protocol, and then inviting those who complete the ozone study to undertake endotoxin challenge. Ozone is a commonly occurring pollutant, and endotoxin is a major component of particulate matter and bioaersols. The response phenotypes we will examine include lung function, airway inflammation, immunophenotyping of airway and circulating monocytes, macrophages and dendritic cells, airway and circulating phagocyte function (oxidative burst and phagocytosis of opsonized zymosan) and mediator secretion. Recruitment will initially be focused on the null and sufficient glutathione-S-transferase M1 (GSTM1) genotype and null vs. sufficient and single nucleotide polymorphisms (SNPs) for nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase (NQO1), with the resulting haplotypes. Other common single nucleotide polymorphisms (SNPs) of interest exist in NF-E2, related factor 2 (NRF2), GSTP1, GSTT1, glutathione peroxdiase (GPX1), Heme oxygenase-1 (HO-1), and Superoxidase dismutase 2 (SOD2), theCD14 gene promoter, TLR2, TLR4; IL-1 , IL-1R, and the TNF gene promoter. While recruitment is focused on GSTM1 and NQO1, allele frequencies of the other genes are high enough that assessment of the effect of these SNPs will be achieved as well. Gene expression profiling using mRNA recovered from airway and circulating cells will also be conducted to identify novel candidate genes that regulate response to ozone and LPS. PUBLIC HEALTH RELEVANCE: Knowledge obtained from this research can be used for mitigation of the effect of environmental pollutants on persons with lung and cardiovascular disease through development of personal mitigation strategies and policymaking. The Clean Air Act requires that the National Ambient Air Quality Standards protect vulnerable populations, including those which genetically define vulnerability. Finally, these studies will also add to fundamental advances in our understanding of the pathophysiology of common human conditions.