Sphingolipids and inflammatory biomarkers of COPD progression in healthy smokers

健康吸烟者 COPD 进展的鞘脂和炎症生物标志物

基本信息

批准号：
9323560
负责人：
RUSSELL Paul BOWLER
金额：
$ 39.63万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9323560
关键词：
Biological Availability Biological Markers Blood Blood Proteins Blood specimen CCL20 gene Cause of Death Ceramides Chronic Chronic Obstructive Airway Disease Clinical Data Development Diagnosis Diagnostic tests Disease Disease Progression Distal Early Intervention Early treatment Fibrinogen Gelatinase B Genetic Genetic study Genotype Goals High Resolution Computed Tomography Inflammatory Intercellular adhesion molecule 1 Interleukin-6 International Intervention Studies Knowledge Lipids Longitudinal Studies Longitudinal cohort Lung diseases Measures Medical Genetics Minority Modeling Molecular Profiling Obstruction Onset of illness Phenotype Plasma Prevention Proteomics Publishing Pulmonary Emphysema Pulmonary Surfactant-Associated Protein D Research Respiratory physiology Risk Risk Factors Sampling Smoker Smoking Specimen Sphingolipids Sphingomyelins Sweden TNF gene Testing Time United States Work X-Ray Computed Tomography adiponectin blood lipid candidate marker clinical biomarkers clinical phenotype cohort disorder risk experimental study follow-up genetic association genetic signature genome wide association study genome-wide imaging biomarker improved molecular phenotype novel novel diagnostics predictive marker prevent protein biomarkers public health relevance smoking cessation

项目摘要

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the US1, 2. Although COPD occurs predominantly in smokers, it is unknown why only a minority of smokers (~20-40%) develop chronic airflow limitation or destruction of distal airspaces (emphysema). Furthermore, most subjects will spend many years in a presymptomatic disease state (pre-COPD) before the onset of disease, even after smoking cessation. Identification of the at-risk presymptomatic current or former smoker is the crucial firt step needed to study early interventions that can prevent the development of COPD and emphysema. In pilot work we have identified multiple novel blood lipid (sphingomyelin and ceramide species) and protein biomarkers of COPD and emphysema. We hypothesize that some of these biomarkers will be stable molecular signature that can identify presymptomatic current and former smokers who are at risk for progression to symptomatic lung disease such as COPD and emphysema. Our proposal will measure candidate biomarkers in previously collected blood from three international longitudinal cohorts (COPDGene, SPIROMICS, and Big3) that contain large numbers of pre-symptomatic former or current smokers without COPD or emphysema, who have genome wide genotyping, and are followed 3-5 years with extensive clinical phenotyping including lung function and qHRCT. The first aim will identify which biomarkers are association with progression of airflow limitation and emphysema in those who do not have COPD at baseline. The second aim will investigate whether these signatures are stable over time and identify the genetic associations contributing to the biomarker signature.

描述（由申请人提供）：慢性阻塞性肺疾病 (COPD) 是美国第三大死亡原因1, 2。虽然 COPD 主要发生在吸烟者中，但尚不清楚为什么只有少数吸烟者 (~20-40%)出现慢性气流受限或远端气腔破坏（肺气肿）。此外，大多数受试者在发病前会处于症状前疾病状态（COPD 前期）。即使在戒烟后，识别有风险的症状前吸烟者是研究预防慢性阻塞性肺病和肺气肿发展的早期干预措施所需的关键的第一步，我们已经确定了多种新型血脂（鞘磷脂）。我们发现，其中一些生物标志物将是稳定的分子特征，可以识别处于危险中的症状前吸烟者和前吸烟者。我们的建议将测量先前从三个国际纵向队列（COPDGene、SPIROMICS 和 Big3）收集的血液中的候选生物标志物，这些队列包含大量未出现 COPD 或当前吸烟者的症状。肺气肿患者进行全基因组基因分型，并进行 3-5 年的广泛临床表型分析，包括肺功能和 qHRCT，第一个目标是确定哪些生物标志物与进展相关。第二个目标是研究这些特征是否随着时间的推移而稳定，并确定导致生物标志物特征的遗传关联。