Functional implications of the TNF

TNF 的功能意义

• 批准号: 7683994
• 负责人: W Michael Foster
• 金额: $ 22.92万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683994
• 关键词: Acute; Adult; Air; Air Pollutants; Alleles; Alveolar Macrophages; Asthma; Biological Assay; Breathing; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Candidate Disease Gene; Cells; Child; Clinical; Collaborations; Common Neoplasm; Cross-Over Studies; Data; Development; Disease; Disease susceptibility; Endotoxins; Environmental Exposure; Epithelial; Ethnic group; Evaluation; Experimental Designs; Exposure to; Extrinsic asthma; Foundations; Future; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genome; Genomics; Genotype; Growth; Haplotypes; Health; Homeostasis; Human; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Institutes; Integration Host Factors; Intervention; Investigation; Irritants; Laboratories; Leadership; Link; Lung; Messenger RNA; Modification; Natural Immunity; Neutrophil Infiltration; Ozone; Patients; Peripheral; Permeability; Physiological; Placebo Control; Placebos; Predisposition; Production; Pulmonary Function Test/Forced Expiratory Volume 1; Reactive Oxygen Species; Reporting; Research; Respiratory physiology; Risk; Rodent; Rodent Model; Role; Science Policy; Single Nucleotide Polymorphism; Stimulus; Suggestion; TNF gene; Testing; Therapeutic; Time; Toxin; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Up-Regulation; Validation; air filter; airway hyperresponsiveness; airway remodeling; base; cohort; cytokine; design; gene environment interaction; human TNF protein; injured airway; lung injury; methacholine; monocyte; mutant; neutrophil; oxidant stress; ozone exposure; potassium peroxymonosulfuric acid; promoter; public health relevance; pulmonary function; racial and ethnic; response; translational study; young adult

DESCRIPTION (provided by applicant): For both adults and young children acute, and repetitive exposure of the airways to air toxins has had led to both transient, and reversible airway injury, but also to remodeling of the airway with impairment of lung growth and pulmonary function. In the completely normal/healthy airway, exposure to O3, a ubiquitous urban air pollutant, induces an inflammatory response that is characterized by increases in epithelial permeability, neutrophil infiltration, and bronchial hyperreactivity. Inhalation of the pleiotropic pro-inflammatory cytokine tumor necrosis factor (TNF) leads to the development of nearly identical responses: hyperresponsiveness of the bronchial airway (AHR), and neutrophil influx. We have recently found a link between these 2 challenges: whereby in single laboratory exposures of young healthy subjects (n=135), a common single nucleotide polymorphism (SNP) in the TNF gene (-308), confers susceptibility to an ambient concentration of O3. Our preliminary results were highly significant and subjects, homozygotic (A/A) or heterozygotic (G/A) for the mutant allele of the TNFa (-308) polymorphism, were 2-times as likely to develop sensitivity to methacholine after O3 as compared to subjects with the wild-type TNFa (-308) (G/G) haplotype. Previous reports suggest that the TNFa (-308) polymorphism leads to increased TNF gene transcription and increased TNFa cytokine production. However, the functional significance of this common TNF polymorphism remains controversial; and moreover, the functional implications of the TNFa (-308) polymorphism in the lung remain undeveloped. We hypothesize that subjects - homozygotic (AA) or heterozygotic (GA) for the mutant allele of the TNFa (-308) promoter polymorphism, will demonstrate enhancement in phenotypic responses to O3 including: increased cellular inflammation and secretion of pro-inflammatory cytokines, enhanced activation of resident alveolar macrophages, and altered bronchial sensitivity, leading to AHR. The proposed research is focused on understanding the interaction between host factors and exposure to a prototypal urban air pollutant. Results from the research plan will help understand the functional contribution of a common polymorphism of TNFa to the initiation inflammatory airway disease, and assign and validate genetic factors that confer vulnerability to O3. PUBLIC HEALTH RELEVANCE. The research plan proposes to develop translational studies in humans that will identify host susceptibility factors that confer vulnerability to the prototypal air pollutant, ozone. The results will have significant impact upon and aid in understanding mechanisms of pro-oxidant lung injury, airway hyperresponsiveness, and adverse health effects that occur during and following exposure to respirable airborne irritants.

描述（由申请人提供）：对于成人和幼儿来说，气道急性和反复接触空气毒素会导致暂时性和可逆性气道损伤，还会导致气道重塑，从而损害肺生长和肺功能。在完全正常/健康的气道中，接触 O3（一种普遍存在的城市空气污染物）会诱发炎症反应，其特征是上皮通透性增加、中性粒细胞浸润和支气管高反应性。吸入多效性促炎细胞因子肿瘤坏死因子 (TNF) 会导致几乎相同的反应的发生：支气管气道 (AHR) 的高反应性和中性粒细胞流入。我们最近发现这两个挑战之间存在联系：在年轻健康受试者 (n=135) 的单次实验室暴露中，TNF 基因 (-308) 中常见的单核苷酸多态性 (SNP) 赋予对环境浓度 O3 的敏感性。我们的初步结果非常显着，与野生型 TNFa (-308) (G/G) 单倍型受试者相比，TNFa (-308) 多态性突变等位基因的纯合 (A/A) 或杂合 (G/A) 受试者在 O3 后对乙酰甲胆碱产生敏感性的可能性是其 2 倍。先前的报告表明 TNFa (-308) 多态性导致 TNF 基因转录增加和 TNFa 细胞因子产生增加。然而，这种常见的 TNF 多态性的功能意义仍然存在争议。此外，TNFa (-308) 多态性在肺中的功能意义尚未得到研究。我们假设，TNFa (-308) 启动子多态性突变等位基因的纯合 (AA) 或杂合 (GA) 受试者将表现出对 O3 的表型反应增强，包括：增加细胞炎症和促炎细胞因子的分泌，增强常驻肺泡巨噬细胞的激活，以及改变支气管敏感性，从而导致 到 AHR。拟议的研究重点是了解宿主因素与典型城市空气污染物暴露之间的相互作用。该研究计划的结果将有助于了解 TNFa 常见多态性对引发炎症性气道疾病的功能贡献，并确定和验证导致 O3 易感性的遗传因素。公共卫生相关性。该研究计划建议开展人类转化研究，以确定导致对典型空气污染物臭氧脆弱性的宿主易感性因素。研究结果将对促氧化肺损伤、气道高反应性以及暴露于可吸入空气刺激物期间和之后发生的不良健康影响的机制产生重大影响并有助于理解。