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

• 批准号: 8997390
• 负责人: RUSSELL Paul BOWLER
• 金额: $ 39.51万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997390
• 关键词: 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; Lung diseases; Measures; Medical Genetics; Minority; Modeling; Molecular Profiling; Obstruction; Onset of illness; Phenotype; Plasma; Prevention; Proteins; Proteomics; Publishing; Pulmonary Emphysema; Pulmonary Surfactant-Associated Protein D; Research; Respiratory physiology; Risk; Risk Factors; Sampling; Smoker; Smoking; Specimen; Sphingolipids; Sphingomyelins; Sweden; Testing; Time; Tumor Necrosis Factor-alpha; United States; Work; X-Ray Computed Tomography; abstracting; adiponectin; blood lipid; clinical phenotype; cohort; disorder risk; follow-up; genetic association; genome wide association study; genome-wide; imaging biomarker; improved; molecular phenotype; novel; novel diagnostics; prevent; public health relevance; research study; smoking cessation

 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（由适用提供）：慢性阻塞性肺疾病（COPD）是US1，2的第三主要死亡原因。尽管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％）会产生慢性气流限制或远端空体（Emphyssema）（Emphysema）。此外，即使在戒烟之后，大多数受试者将在疾病发作之前在疾病发作之前（前）度过很多年。鉴定处于风险的预抑制当前或以前的吸烟者是研究早期干预措施所需的至关重要的FIRT步骤，以防止COPD和肺气肿的发展。在试点工作中，我们已经确定了多种新型血脂（鞘磷脂和神经酰胺物种）和COPD和肺气肿的蛋白质生物标志物。我们假设其中一些生物标志物将是稳定的分子特征，可以鉴定出有症状性肺部疾病（例如COPD和肺气肿）有风险的预抑制当前和前吸烟者。我们的建议将测量先前从三个国际纵向队列（Copdgene，supomics和Big3）中收集的血液中的候选生物标志物，其中包含大量没有COPD或Emphysema的前症状前或目前的吸烟者，它们具有基因组广泛的基因组，并且具有3-5岁的临床临床现象，包括Lung Chantyping（包括Lung lung nugn功能和Qhrct）。第一个目的将确定哪些生物标志物与在基线没有COPD的人中与气流限制和肺气肿的进展相关。第二个目标将研究这些特征是否会随着时间的流逝而稳定，并确定造成生物标志物签名的遗传关联。