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

利用人类暴露于 O3 的情况来研究基因与环境的相互作用

• 批准号: 7829058
• 负责人: David B. Peden
• 金额: $ 48.4万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7829058
• 关键词: Address; Air; Allergens; Animals; Asthma; Biology; Breathing; CD14 gene; Candidate Disease Gene; Cardiovascular Diseases; Cells; Chlorine; Clinical; Clinical Research; Collaborations; Data; Dendritic Cells; Development; Diesel Exhaust; Dose; Endotoxins; Environment; Environmental Medicine; Environmental Pollutants; Exposure to; Functional disorder; GSTP1 gene; GSTT1 gene; Gene Expression Profiling; Gene Family; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genotype; Glutathione; Glutathione S-Transferase; Grant; Haplotypes; Hour; Human; Immune; Immunophenotyping; Individual; Inflammation; Inflammatory Response; Interleukin-1; Intramural Research Program; Knowledge; Lung; Measures; Mediating; Mediator of activation protein; Messenger RNA; NAD(P)H dehydrogenase (quinone) 1, human; NADP; NF-E2-related factor 2; NQO1 gene; National Institute of Environmental Health Sciences; Nitrogen Dioxide; Ozone; Particulate; Particulate Matter; Persons; Phagocytes; Phagocytosis; Phenotype; Positioning Attribute; Protocols documentation; Recovery; Recruitment Activity; Registries; Research; Research Design; Research Ethics Committees; Research Personnel; Respiratory Burst; Respiratory physiology; Role; Sampling; Serum; Single Nucleotide Polymorphism; Smoke; Sputum; TLR2 gene; TLR4 gene; TNF gene; Toxic Environmental Substances; United States National Institutes of Health; Vulnerable Populations; Wood material; Writing; Zymosan; air cleaner; airway inflammation; base; cohort; comparative; environmental agent; experience; exposed human population; granulocyte; heme oxygenase-1; human subject; interest; macrophage; monocyte; novel; pollutant; population based; promoter; public health relevance; repository; response; volunteer

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.

描述（由申请人提供）：此NIEHS挑战授权是针对挑战主题04-ES-102：使用受控人体暴露调查基因x环境相互作用而编写的。正如RFA中所述，“仔细控制人类受试者暴露于低水平的环境毒物，如环境颗粒物，臭氧或柴油机废气，提供了一个机会，有助于加强动物研究和基于人群的研究，以更好地了解遗传学和暴露（GxE）的相互作用。为了解决这个问题，我们将采用两种经批准的暴露方案来评估个体对0.4 ppm臭氧2小时和吸入20，000单位内毒素的反应表型。我们将通过招募志愿者加入臭氧方案，然后邀请完成臭氧研究的志愿者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，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（氧化爆发和调理酵母多糖的吞噬作用）和介质分泌。招募最初将集中在空和足够的谷胱甘肽-S-转移酶M1（GSTM 1）基因型和空与足够的单核苷酸多态性（SNP）的烟酰胺腺嘌呤二核苷酸（磷酸）减少：醌氧化还原酶（NQO 1），以及由此产生的单倍型。其他常见的单核苷酸多态性（SNP）存在于NF-E2、相关因子2（NRF 2）、GSTP 1、GSTT 1、谷胱甘肽过氧化物酶（GPX 1）、血红素加氧酶-1（HO-1）和超氧化物歧化酶2（SOD 2）、CD 14基因启动子、TLR 2、TLR 4、IL-1、IL-1 R和TNF基因启动子中。虽然招募集中在GSTM 1和NQO 1上，但其他基因的等位基因频率足够高，因此也将实现对这些SNP的影响的评估。还将使用从气道和循环细胞中回收的mRNA进行基因表达谱分析，以鉴定调节对臭氧和LPS的反应的新的候选基因。 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策略和政策来缓解环境污染物对肺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，包括那些从基因上界定脆弱性的群体。最后，这些研究也将增加我们对人类常见疾病的病理生理学的理解的根本性进展。