Sphingolipids and inflammatory biomarkers of COPD progression in healthy smokers

 描述(申请人提供)：慢性阻塞性肺疾病(COPD)是美国第三大死因1，2。虽然COPD主要发生在吸烟者中，但尚不清楚为什么只有一小部分吸烟者(~20%-40%)出现慢性气流受限或远端空间破坏(肺气肿)。此外，大多数受试者会在发病前多年处于症状前疾病状态(慢性阻塞性肺病前)，甚至在戒烟后也是如此。确定有风险的症状前现症或曾经吸烟者是研究预防COPD和肺气肿发展的早期干预措施所需的关键的第一步。在试点工作中，我们已经确定了COPD和肺气肿的多种新的血脂(鞘磷脂和神经酰胺种类)和蛋白质生物标志物。我们推测，这些生物标志物中的一些将是稳定的分子标记，可以识别症状前、现吸烟者和既往吸烟者，这些吸烟者有发展为症状性肺部疾病的风险，如COPD和肺气肿。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记物，这些队列包含大量无COPD或肺气肿的症状前吸烟者或当前吸烟者，他们具有全基因组基因分型，并随访3-5年，进行广泛的临床表型分析，包括肺功能和qHRCT。第一个目标是确定哪些生物标志物与基线时没有COPD的患者的气流受限和肺气肿的进展有关。第二个目标将调查这些签名是否随着时间的推移而稳定，并确定对生物标记物签名有贡献的遗传关联。

 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.