Air Pollution and Peripheral Blood Gene Expression in Subjects with Coronary Arte

空气污染与冠心病患者外周血基因表达

• 批准号: 7661193
• 负责人: RALPH J DELFINO
• 金额: $ 29.69万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661193
• 关键词: Acute; Address; Admission activity; Adverse effects; Age; Air; Air Pollutants; Air Pollution; Alleles; Animal Model; Antioxidants; Archives; Area; Biological; Biological Assay; Biological Markers; Biological Process; Blood; Blood Cells; Blood Vessels; Blood specimen; C-reactive protein; CYP1A1 gene; CYP2E1 gene; Caliber; Candidate Disease Gene; Carbon; Cardiac; Cardiovascular system; Cells; Clinical Research; Coagulation Process; Communities; Complex; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Cytochrome P450; Data; Disease Progression; EPHX1 gene; Elderly; Enrollment; Ensure; Environment Design; Enzymes; Epidemiologic Studies; Epidemiology; Exposure to; Foundations; Functional disorder; Funding; Future; Gases; Gene Expression; Gene Proteins; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Glutathione S-Transferase; Health; Home environment; Hospitals; Human; In Vitro; Individual; Infection; Inflammation; Inflammatory; Interleukin-6; Investigation; Knowledge; Lead; Life; Link; Longitudinal Studies; Los Angeles; Manganese Superoxide Dismutase; Measurement; Measures; Mediator of activation protein; Messenger RNA; Microsomal Epoxide Hydrolase; Modification; Morbidity - disease rate; NAD(P)H dehydrogenase (quinone) 1, human; NADP; NQO1 gene; Outcome; Outcome Assessment; Oxidative Stress; Paraoxonase 1; Particle Size; Particulate; Particulate Matter; Pathway interactions; Patients; Peripheral; Peroxidases; Physiological; Platelet Activation; Play; Population; Population Study; Predisposition; Proteins; Public Health; RNA; Recording of previous events; Recruitment Activity; Research; Research Methodology; Retirement; Risk; Role; Sample Size; Sampling; Site; Source; Testing; Thrombosis; Time; Tracer; Transcript; Transcriptional Regulation; Tube; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ultrafine; United States National Institutes of Health; Urban Population; Variant; Whole Blood; Work; Xenobiotic Metabolism; biological adaptation to stress; catalase; clinically relevant; cytokine; endoplasmic reticulum stress; environmental particulate; environmental stressor; gene environment interaction; glutathione peroxidase; heme oxygenase-1; high risk; mRNA Expression; mortality; non-smoker; novel; particle; peripheral blood; pollutant; protein expression; public health relevance; response; tool; trafficking; ultrafine particle

DESCRIPTION (provided by applicant): Numerous studies have shown associations of ambient particulate matter (PM) air pollution with cardiovascular hospital admissions and mortality. The causal pollutant components and physiologic mechanisms for these associations are not fully understood. The objective of the proposed study is to advance knowledge on the importance of particulate air pollution on whole blood gene expression in a high-risk population of elderly people with coronary artery disease (CAD). We propose to determine the expression levels of candidate gene transcripts in subjects from an ongoing panel study, and link the expression results to available data from intensive exposure and health outcome assessments. We collected repeated measures to evaluate acute cardiovascular health effects of exposure to PM, with a focus on ultrafine particles. Enrolled subjects with complete home exposure and health outcome data include 60 elderly nonsmokers living in retirement communities in areas of the Los Angeles air basin with high air pollution levels. Each subject has been followed over a 7-month period with up to 12 blood draws for whole blood total RNA at the same time blood samples were taken for biomarkers of inflammation and oxidative stress. Specific aims are as follows: 1) To assess whether key genes of inflammatory and oxidative stress responses are differentially expressed in peripheral blood of subjects with CAD in relation to air pollutant exposures measured at indoor and outdoor home sites. We hypothesize that the expression level of genes involved in biological pathways relevant to cardiovascular acute responses and disease progression will be altered following higher PM exposures. This will be accomplished with quantitative PCR to test the expression of 42 key genes expected to be up- or down-regulated in response to air pollutants. Genes will include those involved in oxidative stress, antioxidant defense, xenobiotic metabolism, inflammation, coagulation, and endoplasmic reticulum stress. Repeated measures analysis will be used to determine if selected genes change their expression in response to air pollution, adjusted for cell shifts. We will evaluate the relation of gene expression to PM composition and source using detailed measurements at the subjects' retirement communities. We anticipate finding the strongest associations with ultrafine PM and markers of traffic-related air pollution. 2) To evaluate effect modification of relationships in Aim 1 by subject genotypes for proteins involved in oxidative stress or antioxidant responses to air pollutant exposures. We hypothesize that oxidative stress-related polymorphisms will alter the expression of the selected set of genes in response to air pollutant exposures. This exploratory aim will generate preliminary data to plan for larger studies aiming to identify people at potentially heightened susceptibility to adverse effects of air pollution. Results of this study will establish a foundation for additional epidemiologic research involving repeated measurements to yield information about exposure time-dependent gene and protein expression. PUBLIC HEALTH RELEVANCE: We will analyze the relation between exposure to urban air pollution and expression of key genes in peripheral blood cells of a high-risk population of elderly people with a history of coronary heart disease. We will assess the potential of this gene-environment design to become a powerful new tool in population studies aiming to measure biological response to environmental stressors, including air pollutant-induced systemic oxidative stress and inflammation that play a role in adverse cardiovascular outcomes. The relevance to public health is that data will come from the everyday life of a susceptible urban population.

描述（由申请人提供）：许多研究表明，环境颗粒物（PM）空气污染与心血管医院入院和死亡率的关联。这些关联的因果污染物成分和生理机制尚不完全了解。拟议的研究的目的是提高有关颗粒空气污染对全血基因表达的重要性的知识，而冠状动脉疾病老年人（CAD）的高危人群中。我们建议从正在进行的小组研究中的受试者中确定候选基因转录本的表达水平，并将表达结果与来自强化暴露和健康结果评估的可用数据联系起来。我们收集了重复的措施，以评估暴露于PM的急性心血管健康影响，重点是超细颗粒。拥有全部家庭接触和健康结果数据的注册受试者包括60名居住在洛杉矶空中盆地地区退休社区中的非吸烟者，其空气污染水平很高。在7个月的时间里，每个受试者都遵循，全血总RNA最多12次，同时取血样本，以进行炎症和氧化应激的生物标志物。具体目的如下：1）评估炎症性和氧化应激反应的关键基因是否在具有CAD受试者的外周血中差异表达了与在室内和室外住所测得的空气污染物暴露有关的。我们假设在较高的PM暴露后，将改变与心血管急性反应和疾病进展有关的生物途径和疾病进展的基因的表达水平。这将通过定量PCR来实现，以测试预期将对空气污染物响应的42个关键基因的表达。基因将包括参与氧化应激，抗氧化剂防御，异种代谢，炎症，凝结和内质网应激的基因。重复测量分析将用于确定选定的基因是否会因针对细胞移位而调整的空气污染而改变其表达。我们将使用受试者退休社区的详细测量值评估基因表达与PM组成和源的关系。我们预计，与超级紧急PM和交通相关的空气污染标记会发现最牢固的关联。 2）评估受试者基因型在AIM 1中的影响修饰，以评估参与氧化应激或对空气污染物暴露的抗氧化剂反应的蛋白质。我们假设氧化应激相关的多态性会因空气污染物暴露而改变所选基因的表达。这种探索性目标将产生初步数据，以计划进行大型研究，以识别有可能增强空气污染不利影响的人们的敏感性。这项研究的结果将为涉及重复测量的其他流行病学研究建立基础，以产生有关暴露时间依赖性基因和蛋白质表达的信息。公共卫生相关性：我们将分析暴露于城市空气污染的关系与具有冠状动脉疾病史的高危老年人群的外周血细胞中关键基因的表达之间的关系。我们将评估这种基因环境设计的潜力，成为旨在衡量对环境压力源的生物学反应的强大新工具，包括空气污染物诱导的全身氧化应激和炎症，在不良心血管结局中起作用。与公共卫生的相关性是，数据将来自易感城市人口的日常生活。