Investigating the Resilient Smoker

调查有弹性的吸烟者

• 批准号: 10221775
• 负责人: Anita Oh
• 金额: $ 7.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221775
• 关键词: Address; Adverse effects; Adverse event; Affect; Age; Anatomic Surface; Applications Grants; Award; Biological; Biological Factors; Biological Markers; Biological Process; Bronchoscopy; C-reactive protein; California; Cause of Death; Cells; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Consensus; Data; Development; Diagnosis; Diagnostic radiologic examination; Disease; Disease Progression; Disease susceptibility; Dose; Environmental Risk Factor; Epithelial; Epithelial Cells; Event; Exposure to; Fibrinogen; Fostering; Funding; Future; Gases; Gene Expression; Gene Expression Alteration; Genomics; Goals; Health Care Costs; Homeostasis; Knowledge; Longitudinal Studies; Longitudinal cohort study; Lung; Measures; Methods; Morbidity - disease rate; Mucins; National Heart, Lung, and Blood Institute; Onset of illness; Pathway Analysis; Pathway interactions; Physiological; Plasma; Prevalence; Prevention; Prevention strategy; Public Health; Regimen; Research; Research Personnel; Respiratory Signs and Symptoms; Risk Factors; Sampling; San Francisco; Severities; Site; Smoke; Smoker; Smoking; Sputum; Testing; Therapeutic; Tissue-Specific Gene Expression; Tobacco; Tobacco smoke; Training; Training Support; Universities; Vision; Work; airway epithelium; base; bronchial epithelium; career; cigarette smoke; design; health care service utilization; innovation; insight; mortality; non-smoking; novel therapeutics; particle; preservation; prevent; protective factors; pulmonary function; resilience; response; skills; smoking-related lung disease; tobacco smoke exposure; tool; transcriptome sequencing; translational study; treatment strategy

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.

项目概要/摘要 该提案旨在解决相关临床和生物学因素的知识差距 具有抵抗吸烟相关肺部疾病发展的能力以及可能的保护途径 用于开发慢性阻塞性肺病的新疗法和预防方法。烟草烟雾是最多的 慢性阻塞性肺病 (COPD) 的常见环境风险因素，然而，尽管存在这种密切关联，但据估计，只有 当使用肺活量测定标准进行诊断时，15-25% 的吸烟者会患上慢性阻塞性肺病。尚不清楚为什么 一些吸烟者在肺活量测定中对香烟烟雾对肺部的破坏性影响具有“弹性”。一 前提是 COPD 的传统肺活量测定定义可能低估疾病并高估 真正“有弹性”的吸烟者的百分比。具体来说，很大一部分吸烟者不 符合慢性阻塞性肺病 (COPD) 肺量测定标准，但仍有呼吸道症状、病情加重和影像学检查 异常，这表明他们正在经历烟草烟雾暴露的不利影响，并且 表明他们可能并不是真正的“有弹性”。弹性背后的因素之一可能是保护性因素 气道上皮，因为这是肺部暴露于最高浓度的第一个解剖表面 烟草烟雾。我的长期目标是确定与复原力相关的病理生物学机制，而不是 到疾病的发生和进展。我的中心假设是 1）“弹性”可以通过多种方式更好地定义 临床领域以及 2) 气道上皮对慢性烟雾暴露反应的变异性，如 通过基因表达改变来测量，可以改变疾病易感性，并提供对疾病的深入了解 “弹性”机制。我建议在两个特定目标中检验这些假设。目标 1：系统地 使用多个临床领域制定“弹性吸烟者”的新多维定义，并确定 其在 COPD 纵向研究中的患病率和生物学意义。目标 2：识别气道上皮基因 使用 SPIROMICS（NHLBI 资助的多站点）研究与“弹性吸烟者”相关的表达标记 COPD 的纵向队列研究，已获得详细的临床、放射学、生理学数据和 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 完成工作将确定治疗和预防慢性阻塞性肺病的新策略。这种总体方法是创新的，因为 大多数转化研究关注与疾病相关的途径，而不是防止发育 的疾病。该提案直接响应 NHLBI 的优先事项，因为它重点关注目标 1 NHLBI 战略愿景：“了解正常的生物功能和恢复力”。此外，该奖项还将 对 Anita Oh 博士作为加州大学圣玛丽分校临床研究员的培训产生了积极影响 弗朗西斯科（Francisco）为她提供了获取知识和完善她的统计和数据所需的支持 基因组技能可以促进她的研究生涯并朝着成为一名独立研究员的方向发展。