Investigating the Resilient Smoker

调查有弹性的吸烟者

• 批准号: 10022144
• 负责人: Anita Oh
• 金额: $ 9.19万
• 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/10022144
• 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; Epithelium; 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; Respiratory physiology; 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; resilience; response; skills; smoking-related lung disease; 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.

项目摘要/摘要 这项建议旨在解决有关临床和生物因素的知识差距。 对与吸烟相关的肺部疾病的发展具有韧性，并可能通过保护途径 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 慢性阻塞性肺病的常见环境风险因素，然而，尽管存在这种强烈的关联，估计只有 使用肺活量测定诊断标准时，15-25%的吸烟者会患上COPD。目前还不清楚原因 一些吸烟者在呼吸节律上对香烟烟雾对肺部的破坏性影响具有“弹性”。一 前提是COPD的传统肺活量定义可能低估了疾病而高估了 吸烟者的百分比谁是真正的“弹性”。具体地说，相当大比例的吸烟者不 符合COPD肺活量测定标准的患者仍有呼吸道症状、病情加重和X线片 异常，这表明他们正在经历烟草烟雾暴露和 这表明他们可能没有真正的“弹性”。潜在的弹性因素之一可能是保护因素 呼吸道上皮细胞，因为这是第一个暴露在最高浓度的肺解剖表面 烟草烟雾。我的长期目标是确定与韧性相关的病理生物学机制，而不是 与疾病的发生和发展有关。我的中心假设是：1)“韧性”更好地定义为 临床领域和2)呼吸道上皮细胞对慢性烟雾暴露的反应的变异性，如 通过基因表达变化来衡量，可以改变疾病的易感性，并提供对 “弹性”的机制。我建议在两个具体目标上检验这些假设。目标1：系统化 使用多个临床领域开发一个新的多维定义的“弹性吸烟者”并确定 在COPD纵向研究中的患病率和生物学意义。目的2：鉴定呼吸道上皮细胞基因 使用SPIROMICS的与“弹性吸烟者”相关的表达标记，SPIROMICS是NHLBI资助的多站点 COPD的纵向队列研究，已获得详细的临床、放射学、生理数据和 支气管镜下的呼吸道上皮细胞样本。这些目标对公共健康的影响是成功的 完成后将确定治疗和预防慢性阻塞性肺病的新战略。这种总体方法是创新的，因为 大多数翻译研究集中在与疾病相关的途径上，而不是对发育的保护 这种疾病的危害。该提案直接响应NHLBI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弹性”。此外，该奖项将 对Anita oh博士作为加州大学旧金山分校临床研究员的培训产生了积极影响 通过向她提供必要的支持，以获取知识并完善她的统计和 培养她的研究事业和成为一名独立研究人员的进步的基因组技能。