Investigating the Resilient Smoker

项目总结/摘要 该提案旨在解决有关相关临床和生物学因素的知识缺口 对吸烟相关的肺部疾病的发展具有弹性， 用于开发COPD的新疗法和预防方法。烟草烟雾是最 COPD的一个常见环境风险因素，然而，尽管有这种强烈的相关性，据估计， 当使用肺量测定标准进行诊断时，15-25%的吸烟者将发展为COPD。原因不明 一些吸烟者对香烟烟雾的损害性肺效应具有呼吸量测定“弹性”。一 前提是COPD的传统肺功能测定定义可能低估疾病，高估 真正“有弹性”的吸烟者的百分比。特别是，很大一部分吸烟者不吸烟， 符合COPD的肺功能测定标准，但仍有呼吸道症状、加重和放射学检查 异常，这表明他们正在经历烟草烟雾暴露的不良影响， 表明它们可能不是真正的“弹性”。支撑弹性的一个因素可能是保护性因素， 因为这是肺的第一个暴露于最高浓度的 烟草烟雾。我的长期目标是确定与恢复力相关的病理生物学机制， 疾病的发生和发展。我的中心假设是：1）“弹性”更好地定义为多个 临床领域和2）气道上皮细胞对慢性烟雾暴露的反应的变异性， 通过基因表达改变来测量，可以改变疾病的易感性，并提供对 “韧性”机制。我建议在两个具体目标中检验这些假设。目标1：系统化 使用多个临床领域制定“弹性吸烟者”的新多维定义，并确定 慢性阻塞性肺疾病纵向研究中其患病率和生物学意义。目的2：鉴定气道上皮基因 使用SPIROMICS，一个由NHLBI资助的多位点研究项目， COPD纵向队列研究，已获得详细的临床、影像学、生理学数据， 气道上皮细胞的支气管镜样本。这些目标对公共卫生的影响是成功的， 完成后将确定治疗和预防COPD的新策略。这一总体方法是创新的，因为 大多数转化研究集中在与疾病相关的途径，而不是保护免受发展 疾病。该提案直接响应了《国家法律文书》的优先事项，因为它侧重于目标1， NHLBI战略愿景：“了解正常的生物功能和恢复力”。此外，该奖项将 作为加州旧金山大学的临床研究员， 弗朗西斯科，通过为她提供必要的支持，以获得知识和完善她的统计和 基因组技能，以促进她的研究生涯并朝着成为独立研究人员的方向取得进展。

PROJECT SUMMARY/ABSTRACT This proposal seeks to address a gap in knowledge about the clinical and biological factors that are associated with resilience to the development of smoking-related lung disease and protective pathways that may be leveraged to develop new therapies and preventative approaches for COPD. Tobacco smoke is the most common environmental risk factor for COPD, however despite this strong association, it is estimated that only 15-25% of smokers will develop COPD when using spirometric criteria for the diagnosis. It is uncertain why some smokers are spirometrically “resilient” to the damaging pulmonary effects of cigarette smoke. One premise is that the traditional spirometric definition of COPD may underestimate disease and overestimate the percentage of smokers who are truly “resilient”. Specifically, a significant proportion of smokers who do not meet spirometric criteria for COPD still have respiratory symptoms, exacerbations, and radiographic abnormalities, which suggests they are experiencing adverse effects from tobacco smoke exposure and indicate they may not be truly “resilient.” One factor underlying resilience may be protective factors in the airway epithelium since this is the first anatomic surface of the lung exposed to the highest concentration of tobacco smoke. My long-term goal is to identify pathobiological mechanisms related to resilience as opposed to disease onset and progression. My central hypotheses are that 1)“resilience” is better defined using multiple clinical domains and that 2)variability in the airway epithelial response to chronic smoke exposure, as measured by gene expression alterations, can modify disease susceptibility, and provide insight into the mechanisms of “resilience.” I propose to test these hypotheses in two specific aims. Aim 1: Systematically develop a new multidimensional definition of a “resilient smoker” using multiple clinical domains and determine its prevalence and biological significance in a longitudinal study of COPD. Aim 2: Identify airway epithelial gene expression markers associated with the “resilient smoker” using SPIROMICS, an NHLBI-funded multi-site longitudinal cohort study of COPD which has obtained detailed clinical, radiographic, physiological data, and bronchoscopic samples of airway epithelial cells. The public health impact of these aims is that successful completion will identify new strategies to treat and prevent COPD. This overall approach is innovative because most translational studies focus on pathways associated with disease rather than protection from development of the disease. This proposal is directly responsive to NHLBI priorities because it focuses on Objective 1 the NHLBI Strategic Vision: “Understand normal biological function and resilience”. Furthermore, this award will have a positive impact on Dr. Anita Oh's training, as a clinical fellow at the University of California San Francisco, by providing her with the support necessary to acquire knowledge and refine her statistical and genomic skills to foster her research career and progress towards becoming an independent researcher.