Functional implications of the TNF

TNF 的功能意义

基本信息

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
项目类别：
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

项目摘要

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）：对于成年和幼儿急性，以及气道对空气毒素的重复暴露导致了短暂的和可逆的气道损伤，而且还导致了肺部生长和肺功能的损害，还导致了气道的重塑。在完全正常/健康的气道中，暴露于无处不在的城市空气污染物O3会诱导炎症反应，其特征是上皮通透性，中性粒细胞浸润和支气管支气管高反应性的增加。吸入多效性促炎性细胞因子肿瘤坏死因子（TNF）导致几乎相同的反应的发展：支气管气道（AHR）（AHR）和中性粒细胞涌入的高反应性。我们最近发现了这两个挑战之间的联系：在TNF基因（-308）中，在单一实验室暴露年轻的健康受试者（n = 135）中，一种常见的单核苷酸多态性（SNP），赋予了环境浓度O3的易感性。我们的初步结果非常显着，对于TNFA（-308）多态性的突变等位基因的受试者，纯合（A/A）或杂合子（G/A），与野生型TNFA TNFA（-g308）相比，O3之后对甲基苯胺的敏感性与O3后的甲基苯胺相同2次（g）（g/g）（g/g），这可能是2次。先前的报道表明，TNFA（-308）多态性导致TNF基因转录增加并增加TNFA细胞因子的产生。但是，这种常见的TNF多态性的功能意义仍然存在争议。而且，肺中TNFA（-308）多态性的功能含义仍然没有开发。 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到啊。拟议的研究重点是了解宿主因素与暴露于原型城市空气污染物之间的相互作用。研究计划的结果将有助于了解TNFA常见多态性对炎症气道疾病的功能贡献，并分配和验证赋予O3脆弱性的遗传因素。公共卫生相关性。该研究计划提议在人类中开发翻译研究，以确定宿主的敏感性因素，以赋予原型空气污染物臭氧。结果将对促氧化肺损伤，气道高反应性以及暴露于可吸入的空气流刺激物期间发生的促氧化肺损伤，气道高反应和不良健康影响的机制产生重大影响并有助于理解机制。