Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers

描述(申请人提供)：吸烟是已知的导致肺部疾病发展的最大单一危险因素，是发展为肺气肿和特发性肺纤维化的主要危险因素。虽然肺纤维化和肺气肿可以在同一个体中共存，但我们最近的报告表明，在吸烟者中，亚临床特发性肺纤维化(IPF)与总肺活量和肺气肿呈负相关。加之大多数患有IPF的既往吸烟者没有肺气肿的放射学证据，这一事实表明，这些疾病模式很可能是由于反映了独特的个人易感性的不同吸烟后果及其相关的不同致病途径(S)。我们已经组建了一个研究团队，他们高效和协同地工作，以更好地理解香烟烟雾导致纤维化或肺气肿，或两者兼有的机制(S)。我们整合了COPD和IPF社区调查人员的专业知识，包括基础和翻译方面的专业知识，共同应对这一重要挑战。实现这一主要目标将对肺学界产生重大影响，因为我们希望揭开慢性阻塞性肺疾病和肺间质纤维化新的分子靶点和/或治疗方法(S)。我们将试图通过解决以下项目和核心来达到我们的目标：1)自噬在肺气肿和纤维化中的稳态作用2)转化生长因子-β1和香烟烟雾在纤维化和肺气肿中的遗传修饰物3)COPD和IPF的遗传学和表观遗传学4)吸烟者患有实质性肺疾病核心的临床结果和分子表型：1)管理核心2)呼吸计算发现核心3)临床生物库核心4)小鼠模型和分子分析核心

DESCRIPTION (provided by applicant): Cigarette smoking is the greatest known single risk factor for the development of lung disease, being a dominant risk for the development of both emphysema and idiopathic pulmonary fibrosis. While pulmonary fibrosis and emphysema can co-exist in the same individual, our recent report indicates that subclinical idiopathic pulmonary fibrosis (IPF) is inversely associated with total lung capacity and emphysema in smokers. Along with the fact that most former smokers with IPF do not have radiographic evidence of emphysema, suggests that these patterns of disease are likely to be due to distinct consequences of smoking reflecting unique individual susceptibilities, and its associated differential pathogenetic pathway(s). We have assembled a team of investigators who have worked efficiently and synergistically to better understand the mechanism(s) by which cigarette smoke can induce either fibrotic or emphysematous, or both phenotype. We have integrated the expertise of investigators from COPD and IPF community, both basic and translational, to come together to tackle this important challenge. The impact of reaching this major goal will be significant in the pulmonary community as we hope to unravel new molecular targets and/or treatment(s) for COPD and IPF. We will attempt to reach our goals by the addressing the following projects and cores: Projects: 1) Homeostatic Role of Autophagy in Lung Emphysema and Fibrosis 2) Genetic Modifiers of TGF-Beta1 and Cigarette Smoke in Fibrosis and Emphysema 3) Genetics and Epigenetics of COPD and IPF 4) Clinical Outcomes and Molecular Phenotypes in Smokers with Parenchymal Lung Disease Cores: 1) Administrative Core 2) Respiratory Computational Discovery Core 3) Clinical Biorepository Core 4) Murine Models and Molecular Analysis Core