Clinical Implications, Genomics, and Transcriptions of Mucus Plugging in Smokers

吸烟者粘液堵塞的临床意义、基因组学和转录

• 批准号: 10231232
• 负责人: MICHAEL H. CHO
• 金额: $ 81.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-09 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231232
• 关键词: Acute; Affect; Bronchial Tree; Cause of Death; Cessation of life; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Coughing; Cutis Laxa; Data; Data Reporting; Development; Disease; Enrollment; Epithelial Cells; Evaluation; Exudate; Flare; Functional disorder; Gene Expression; General Population; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genetic study; Genomics; Genotype; Hyperplasia; Image; Knowledge; Lung; Lung diseases; Measures; Medical Genetics; Meta-Analysis; Metaplastic Cell; Military Personnel; Modeling; Mucous body substance; Nasal Epithelium; Outcome; Patient Self-Report; Phase; Phenotype; Plug-in; Population; Process; Production; Pulmonary Emphysema; Reporting; Reproducibility; Respiratory Signs and Symptoms; Risk Factors; Scanning; Severity of illness; Shortness of Breath; Smoker; Smoking; Sputum; Structure of parenchyma of lung; Surrogate Endpoint; Susceptibility Gene; Syndrome; Testing; Tissue Sample; Tissue-Specific Gene Expression; Trans-Omics for Precision Medicine; United States; Visual; X-Ray Computed Tomography; airway obstruction; alpha 1-Antitrypsin Deficiency; asthmatic; base; bronchial epithelium; chest computed tomography; cigarette smoke-induced; cigarette smoking; clinical investigation; clinically relevant; cohort; differential expression; disease heterogeneity; disease phenotype; epidemiology study; follow-up; gene discovery; genetic makeup; genetic variant; genome sequencing; genome wide association study; genome-wide; hazard; insight; longitudinal analysis; lung cancer screening; mortality; mucus clearance; mucus hypersecretion; novel therapeutics; persistent symptom; pulmonary function; transcriptomics; whole genome

Project Summary/Abstract Airflow obstruction is a defining pathophysiologic feature of chronic obstructive pulmonary disease (COPD). COPD affects approximately 28.9 million people and is the 3rd leading cause of death in the United States. Although the main risk factor for COPD is cigarette smoking, there is evidence of genetic susceptibility as well. Monogenic syndromes —Alpha-1 antitrypsin deficiency and cutis laxa— have emphysema, a COPD phenotype, as part of their manifestations. An understudied pathophysiologic feature leading to airflow obstruction in COPD is mucus dysfunction. Cigarette smoke-induced mucus dysfunction results in increased production of and reduced clearance of mucus leading to its accumulation in the airways and plug formation, which in turn leads to airflow obstruction. Lung tissue studies demonstrated that occlusion of small airways by mucous exudates are related to disease severity and mortality, underscoring the clinical relevance of mucus dysfunction. The main limitation of current clinical and genetic studies of mucus dysfunction in COPD is that they have relied on self-reported data such as chronic cough and phlegm and lung tissue to reflect this abnormality. In this proposal we will visually identify and score mucus plugging on chest computed tomography (CT) from subjects enrolled into the COPDGene, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End- points (ECLIPSE) and Detection of Early Lung Cancer Among Military Personnel (DECAMP)-2 studies —large cohorts of smokers with and without COPD. In Aim 1, we will perform a visual scoring in phases 1, 2 and 3 CT scans of the COPDGene Study. We will then determine the factors associated with 10-yr changes in CT- identified mucus plugging as well as the associations of this imaging feature to acute respiratory disease episodes and death. In Aim 2, we will score mucus plugging in all baseline ECLIPSE CT scans and use the scores of COPDGene from Aim 1 to perform genome-wide association studies to determine the common and rare genetic variants related to CT-identified mucus plugging. We will utilize genome-wide genotyping, imputation, and whole-genome sequencing data for gene discovery. We will then test the associations between CT-identified mucus plugging and common and rare genetic variants using meta-analysis in COPDGene and ECLIPSE cohorts. Finally, in Aim 3 we will score mucus plugging on CT scans from smokers enrolled into DECAMP-2 Study. The transcriptomic analysis will be performed in collected bronchial and nasal epithelial cells to identify gene expression differences for imaging-based mucus plugging. We believe that this project will increase the clinical and genetic understanding of mucus dysfunction, a clear gap in COPD, and will provide a validated imaging assessment that can be used for clinical and epidemiologic investigation.

项目总结/摘要 气流阻塞是慢性阻塞性肺疾病（COPD）的一个明确的病理生理特征。 COPD影响约2890万人，是美国第三大死亡原因。 虽然COPD的主要危险因素是吸烟，但也有遗传易感性的证据。 单基因综合征-α-1抗胰蛋白酶缺乏和皮肤拉克萨-有肺气肿，一种慢性阻塞性肺病 表型，作为其表现的一部分。一种未充分研究的导致气流的病理生理特征 COPD中的阻塞是粘液功能障碍。香烟烟雾引起的粘液功能障碍导致 粘液的产生和减少的粘液清除导致其在气道中的积聚和堵塞形成， 这又导致气流阻塞。肺组织研究表明， 粘液渗出物与疾病的严重程度和死亡率有关，强调了粘液分泌物的临床相关性。 功能障碍目前COPD粘液功能障碍的临床和遗传学研究的主要局限性在于， 他们依靠自我报告的数据，如慢性咳嗽、痰和肺组织来反映这一点 异常 在本提案中，我们将在胸部计算机断层扫描（CT）上对粘液堵塞进行视觉识别和评分， 入组COPD基因的受试者，纵向评估COPD以确定预测性替代终点- 点（ECLIPSE）和军人早期肺癌检测（DECAMP）-2项研究-大型 有和没有COPD的吸烟者队列。在目标1中，我们将在第1、2和3阶段CT中进行视觉评分 COPDGene研究的扫描图。然后，我们将确定与CT 10年变化相关的因素- 确定了粘液堵塞以及这种成像特征与急性呼吸道疾病的相关性 事件和死亡。在目标2中，我们将对所有基线ECLIPSE CT扫描中的粘液堵塞进行评分，并使用 目标1中的COPD基因评分进行全基因组关联研究，以确定常见的 与CT鉴定的粘液堵塞有关的罕见遗传变异。我们将利用全基因组基因分型， 用于基因发现的全基因组测序数据。然后我们将测试 使用荟萃分析确定的粘液堵塞与常见和罕见遗传变异之间的关系， COPDGene和ECLIPSE队列。最后，在目标3中，我们将在吸烟者的CT扫描上对粘液堵塞进行评分 入组DECAMP-2研究。将在收集的支气管和鼻腔中进行转录组学分析。 上皮细胞，以鉴定用于基于成像的粘液堵塞的基因表达差异。我们认为这 该项目将增加对粘液功能障碍的临床和遗传理解，这是COPD的一个明显差距， 提供可用于临床和流行病学调查的经验证的成像评估。