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

描述(由申请人提供)：本NIEHS挑战资助金是针对挑战主题04-ES-102：使用受控的人类暴露研究基因x环境相互作用而撰写的。正如RFA中所述，“仔细控制人类受试者对低水平环境毒物的暴露，如环境颗粒物、臭氧或柴油废气，提供了一个机会，有助于加强动物研究和基于人群的研究，以更好地了解遗传和暴露(GxE)之间的相互作用。为了解决这个问题，我们将采用两种获得批准的暴露方案，以获取个体在0.4ppm臭氧中持续2小时的反应表型，以及吸入20000个单位的内毒素。我们将通过招募志愿者加入臭氧议定书，然后邀请那些完成臭氧研究的人进行内毒素挑战来实现这一点。臭氧是一种常见的污染物，内毒素是颗粒物和生物气溶胶的主要成分。我们将检测的反应表型包括肺功能、呼吸道炎症、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(氧化爆发和吞噬调理酵母多糖)和介质分泌。招募最初将集中在谷胱甘肽-S-转移酶M1(GSTM1)缺失和充足的基因型以及烟酰胺腺嘌呤二核苷酸(磷酸)还原的缺失和充分的单核苷酸多态(SNPs)：苯醌氧化还原酶(NQO1)，以及由此产生的单倍型。其他常见的单核苷酸多态(SNPs)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)和超氧化物歧化酶2(SOD2)、CD14基因启动子TLR2、TLR4、IL-1、IL-1R和肿瘤坏死因子基因启动子。虽然招募的重点是GSTM1和NQO1，但其他基因的等位基因频率足够高，因此也将对这些SNP的影响进行评估。还将使用从呼吸道和循环细胞中提取的mRNA进行基因表达谱分析，以确定调节对臭氧和内毒素反应的新候选基因。 公共卫生相关性：从这项研究中获得的知识可用于通过制定个人缓解战略和政策制定来缓解环境污染物对患有肺病和心血管疾病的人的影响。《清洁空气法》要求国家环境空气质量标准保护脆弱人群，包括那些从基因上定义脆弱性的人群。最后，这些研究还将促进我们对常见人类疾病的病理生理学的理解。

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.