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Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers

吸烟者纤维化和肺气肿的独特和重叠途径

基本信息

批准号：
8476322
负责人：
Augustine M Choi
金额：
$ 234.56万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-06 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8476322
关键词：
Address Autophagocytosis Basic Science Biochemical Bleomycin Bronchoscopy Chest Chronic Obstructive Airway Disease Chronic lung disease Cigarette Smoker Cigarette smoke-induced emphysema Clinical Clinical/Radiologic Communities DNA Methylation Data Defect Development Disease Epidemiology Epigenetic Process Exhibits Experimental Designs Experimental Models Factor V Fibrosis Future Gene Expression Genetic Goals Hamman-Rich syndrome Health Homeostasis In Vitro Individual Lead Lung Lung diseases Mediating Mitochondria Modeling Modification Molecular Analysis Molecular Target Mus Outcome Pathogenesis Pathway interactions Patients Pattern Phenotype Pre-Clinical Model Predisposition Proteins Published Comment Pulmonary Emphysema Pulmonary Fibrosis Reactive Oxygen Species Regulation Reporting Research Personnel Resistance Risk Risk Factors Role Science of genetics Sirolimus Smoker Smoking Smoking History Structure of parenchyma of lung Testing Tissue Sample Total Lung Capacity Transforming Growth Factors Visual Work X-Ray Computed Tomography abstracting base biobank cigarette smoke-induced cigarette smoking cigarette smoking cohort disease phenotype effective therapy human TGFB1 protein interest mTOR protein molecular phenotype programs public health relevance respiratory response therapy development

项目摘要

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

描述（由申请方提供）：吸烟是发生肺部疾病的最大已知单一风险因素，是发生肺气肿和特发性肺纤维化的主要风险。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，亚临床特发性肺纤维化（IPF）与吸烟者的总肺活量和肺气肿呈负相关。沿着大多数IPF既往吸烟者没有肺气肿的影像学证据这一事实，表明这些疾病模式可能是由于吸烟的不同后果，反映了独特的个体易感性及其相关的差异性致病途径。我们已经组建了一个研究团队，他们有效地协同工作，以更好地了解香烟烟雾可以诱导纤维化或肺气肿或两种表型的机制。我们整合了来自COPD和IPF社区的研究人员的专业知识，包括基础知识和转化知识，共同应对这一重要挑战。实现这一主要目标将对肺部社区产生重大影响，因为我们希望揭示COPD和IPF的新分子靶点和/或治疗方法。我们将尝试通过解决以下项目和核心来实现我们的目标：项目：1）自噬在肺气肿和纤维化中的稳态作用2）TGF-β 1的遗传修饰物和香烟烟雾在纤维化和肺气肿中的作用3）COPD和IPF的遗传学和表观遗传学4）患有实质性肺病核心的吸烟者的临床结局和分子表型：1）管理核心2）呼吸计算发现核心3）临床生物储备核心4）小鼠模型和分子分析核心