Linking airway genomics to the pathogenesis and clinical heterogeneity of COPD

将气道基因组学与 COPD 的发病机制和临床异质性联系起来

• 批准号: 7691772
• 负责人: Marc Elliott Lenburg
• 金额: $ 73.77万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691772
• 关键词: Affect; Aftercare; Alternative Splicing; Area; Bioinformatics; Biological Assay; Biometry; Boston; Breathing; British Columbia; Bronchoscopy; Cause of Death; Cells; Chest; Chronic Obstructive Airway Disease; Clinical; Collaborations; Collection; Complex; Computing Methodologies; Data; Data Set; Development; Diagnosis; Disease; Disease Progression; Disease susceptibility; Epithelial; Epithelial Cells; Evaluation; Exhibits; Exons; Framingham Heart Study; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Determinism; Genetic Markers; Genome; Genomics; Genotype; Health; Health Expenditures; Heterogeneity; Hospitalization; Image; Immune response; Individual; Injury; Interdisciplinary Study; Link; Lung; Lung Transplantation; Measurement; Measures; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Natural History; Obstruction; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Play; Process; Public Health; Pulmonary Emphysema; Pulmonary Function Test/Forced Expiratory Volume 1; RNA; RNA analysis; Research; Research Personnel; Resected; Resources; Respiratory physiology; Risk; Role; SNP genotyping; Sampling; Series; Severities; Smoke; Smoker; Smoking; Specimen; Structure of parenchyma of lung; Surface; Symptoms; Testing; Therapeutic; Thick; Tissue Sample; Tissues; United States; Universities; Variant; Work; X-Ray Computed Tomography; abstracting; airway epithelium; alveolar destruction; base; bronchial epithelium; cigarette smoking; cohort; disorder subtype; functional decline; genetic variant; genome-wide; innovation; insight; member; mortality; novel; novel strategies; prevent; pulmonary function; pulmonary function decline; small airways disease; tool; trait

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and its mortality rate is expected to climb steadily over the next 20 years. In the US, this condition causes over 700,000 hospitalizations per year and leads to $20-26 billion in annual health care expenditures. There is currently no cure for COPD, and the limited therapies currently available mainly reduce symptoms rather than reverse the disease or prevent its progression. While the role cigarette smoke plays in COPD is undisputed, the mechanism by which inhaled smoke contributes to disease pathogenesis remains unclear. One of the major barriers to the development of new approaches to diagnose and manage COPD is the clinical heterogeneity displayed by COPD patients. While COPD has been defined as a disease state characterized by airflow limitation that is not fully reversible, there are diverse clinical, radiographic, and pathologic findings that likely reflect different underlying molecular and pathogenic disease mechanisms. Cigarette smoke causes an airway-wide "field of injury", and gene expression in bronchial airway cells of smokers obtained by brushings at bronchoscopy reflects both this injury and subsequent disease-specific processes. This proposal examines the hypothesis that determining the gene-expression profile of airway epithelial cells in individuals with and without COPD will provide insights into the molecular pathogenesis of COPD and specific COPD-related traits, including degree of airflow obstruction, emphysema, small airways disease, and the rate of disease progression. Alterations in airway gene and microRNA expression will be used to define the underlying pathways that are perturbed by COPD, and to define novel molecular subclasses of COPD that may contribute to the clinical diversity of the disease. Patterns of airway gene expression will be linked to longitudinal decline in lung function, providing a way to identify individuals at risk for rapid disease progression and an understanding of the mechanisms responsible for variations in their rate of functional decline. How the expression of COPD-related airway gene-expression profiles change during disease progression within lung tissue will elucidate dynamic disease-related processes. The reversibility of these gene expression changes upon treatment with various existing and novel COPD drugs will determine whether airway gene expression signatures can serve as an intermediate marker for evaluating COPD treatments. Finally, the identification of heritable genetic variants that influence the underlying pathways that are responsible for COPD-specific gene expression changes, and testing their ability to identify individuals at risk for COPD, will result in genetic markers of disease susceptibility and progression. The proposed work applies powerful whole-genome exon level and microRNA expression platforms and a variety of novel computational methodologies to samples from a series of large, unique, and well-characterized existing cohorts, and will result in an unprecedented and detailed view of the molecular processes that contribute to COPD pathogenesis. (End of Abstract)

描述（由申请人提供）： 慢性阻塞性肺疾病（COPD）是美国第四大死亡原因，其死亡率预计在未来20年内稳步攀升。在美国，这种疾病每年导致超过70万例住院治疗，并导致每年200 - 260亿美元的医疗保健支出。目前还没有治愈COPD的方法，目前可用的有限疗法主要是减轻症状，而不是逆转疾病或防止其进展。虽然香烟烟雾在COPD中的作用是无可争议的，但吸入烟雾导致疾病发病机制的机制仍不清楚。开发诊断和管理COPD的新方法的主要障碍之一是COPD患者表现出的临床异质性。虽然COPD已被定义为一种以气流受限为特征的疾病状态，但不完全可逆，但有多种临床、影像学和病理学发现可能反映了不同的潜在分子和致病性疾病机制。香烟烟雾导致气道范围的“损伤领域”，通过支气管镜检查获得的吸烟者支气管气道细胞中的基因表达反映了这种损伤和随后的疾病特异性过程。该提案检验了以下假设：确定COPD患者和非COPD患者气道上皮细胞的基因表达谱将为COPD的分子发病机制和特定COPD相关特征提供见解，包括气流阻塞程度、肺气肿、小气道疾病和疾病进展速度。气道基因和microRNA表达的改变将用于确定受COPD干扰的潜在途径，并确定可能导致疾病临床多样性的COPD新分子亚类。气道基因表达模式将与肺功能的纵向下降相关，从而提供了一种识别疾病快速进展风险个体的方法，并了解了导致其功能下降速率变化的机制。COPD相关气道基因表达谱在肺组织疾病进展过程中的变化将阐明疾病相关的动态过程。这些基因表达变化在用各种现有和新型COPD药物治疗后的可逆性将决定气道基因表达特征是否可以用作评估COPD治疗的中间标志物。最后，识别影响COPD特异性基因表达变化的潜在途径的遗传性遗传变异，并测试其识别COPD风险个体的能力，将产生疾病易感性和进展的遗传标记。拟议的工作将强大的全基因组外显子水平和microRNA表达平台以及各种新颖的计算方法应用于来自一系列大型，独特和充分表征的现有队列的样本，并将导致对COPD发病机制的分子过程的前所未有的详细视图。(End摘要）