Mechanisms of COPD Subphenotype Development

COPD 亚表型发展机制

• 批准号: 8497712
• 负责人: Michael Bradley Drummond
• 金额: $ 16.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497712
• 关键词: Affect; Ancillary Study; Animal Model; Anti-Retroviral Agents; Apoptosis; Apoptotic; Area; Award; Biological; Biological Assay; Biometry; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cause of Death; Cessation of life; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Investigator; Clinical Research; Cohort Studies; Critical Care; Data; Dedications; Development; Development Plans; Disease; Disease susceptibility; Ensure; Environment; Epidemiology; Epithelial; Epithelial Cells; Experimental Models; Faculty; Goals; HIV; HIV-1; High Resolution Computed Tomography; Human; Image; Immunology; Individual; Infection; Inflammation; Inflammatory; Intervention; Lead; Lung; Lung diseases; Measures; Mediating; Medicine; Mentors; Mentorship; Methods; Minority; Modeling; Motivation; Obstruction; Participant; Pathway interactions; Peripheral; Population; Predisposition; Procedures; Process; Productivity; Pulmonary Emphysema; Recording of previous events; Research; Research Personnel; Research Project Grants; Research Proposals; Respiratory physiology; Risk; SECTM1 gene; Sampling; Serum; Severities; Smoker; Smoking; Structure; Symptoms; Testing; Thick; Time; Tobacco smoke; Training; Treatment outcome; Universities; Up-Regulation; Viral; Viral Load result; Viremia; Virus Diseases; airway inflammation; airway remodeling; base; career; career development; cigarette smoking; clinical care; cohort; cytokine; endoplasmic reticulum stress; experience; human data; improved; inflammatory marker; lung imaging; meetings; member; mortality; response; role model

DESCRIPTION (provided by applicant): While the causal relationship between cigarette smoke exposure and development of chronic obstructive pulmonary disease (COPD) has been firmly established, the mechanisms underlying differing susceptibilities and manifestations of lung disease in humans remains unclear. Experimental models suggest that cigarette smoke exposure induces pro-inflammatory cytokines and increased apoptosis within the lung, leading to airways remodeling and emphysema-predominant subphenotypes of COPD. Chronic viral infection has been demonstrated to augment the development of emphysema in animal models. In this application, we plan to investigate these potential mechanisms for COPD subphenotype development in a group of individuals from the Study of HIV Epidemiology in Lung Disease (SHIELD). SHIELD is an ongoing cohort study of individuals at-risk or with HIV that seeks to understand how HIV infection affects various lung diseases. In this proposal, we will conduct an ancillary study that explores proposed mechanisms of COPD development in this population with chronic viral infection. Specifically, we will correlate the presence of obstruction on spirometric testing with high resolution computed tomography (HRCT) quantification of airways remodeling and emphysema in 500 SHIELD participants. We will assess the effect of HIV infection on HRCT scores in individuals with and without obstruction. We will also collect bronchoalveolar lavage and airway epithelial brushings in a subset of participants. These biological samples will be used to assay inflammatory and apoptotic markers, correlating the levels with presence of obstruction, HRCT quantification of airways remodeling/emphysema and serum levels of viremia. We will identify 20 individuals initiating anti-retroviral therapy (ART) in the setting of clinical care and obtain HRCT quantification and bronchoscopic samples before and after initiating ART to determine the effects of ART and viremic reduction on these measures. Ultimately, the information gained from this application will contribute to the understanding of mechanisms underlying the development of COPD subphenotypes. Additionally, these data will allow for a better understanding of the impact of chronic viral infections, specifically HIV, on COPD susceptibility. The applicant, a current K12 awardee, has demonstrated a dedication to a career in clinical research. Early in his career, he has demonstrated motivation and productivity in his ongoing research endeavors. This application is structured to allow the candidate to achieve his long term career goal of becoming an independent clinical investigator exploring potential therapies that improve the treatment and outcomes of those affected by COPD. In the immediate timeframe, this proposal would allow the applicant dedicated time to conduct the outlined research project as well as pursue didactic training in advanced biostatistics and immunology relevant to this project and future research plans. Additionally, the data generated from this research proposal will form the basis for an R01 application. The research career development plan for this applicant includes a structured approach to mentoring, didactic coursework focused on specific research goal, participation in local and national meetings, and identification and regular assessment of career milestones. The research environment provided by Johns Hopkins University as well as the mentorship team outlined in this application will assist in a successful completion of the candidate's career and research goals. The Division of Pulmonary and Critical Care Medicine and Johns Hopkins University have a long history of training successful clinical researchers in a supportive and collaborative environment. The pre-existing structure of SHIELD, the umbrella project for this application, will ensure that study procedures will be completed within the timeframe of this award. We have assembled a mentoring team of established faculty with many years of productive research experience and substantial prior mentoring experience. Each has distinct, complementary strengths in areas of research relevant to this proposal. In addition, each member of the mentoring committee serves as an excellent role model for the applicant's career development into an independent investigator.

描述（由申请方提供）：虽然香烟烟雾暴露与慢性阻塞性肺疾病（COPD）发生之间的因果关系已经确定，但人类肺部疾病不同易感性和表现的潜在机制仍不清楚。实验模型表明，香烟烟雾暴露诱导促炎细胞因子和肺内细胞凋亡增加，导致气道重塑和COPD的肺气肿为主的亚表型。在动物模型中，慢性病毒感染已被证明会增加肺气肿的发展。在本申请中，我们计划在来自肺部疾病HIV流行病学研究（SHIELD）的一组个体中研究COPD亚表型发展的这些潜在机制。SHIELD是一项针对高危人群或HIV感染者的持续队列研究，旨在了解HIV感染如何影响各种肺部疾病。在本提案中，我们将进行一项辅助研究，探讨慢性病毒感染人群中COPD发展的拟议机制。具体而言，我们将在500名SHIELD参与者中将肺功能测定试验中阻塞的存在与气道重塑和肺气肿的高分辨率计算机断层扫描（HRCT）定量相关联。我们将评估HIV感染对梗阻和非梗阻个体HRCT评分的影响。我们还将收集一部分参与者的支气管肺泡灌洗和气道上皮刷检。这些生物样本将用于测定炎症和凋亡标志物，将水平与阻塞的存在、气道重塑/肺气肿的HRCT定量和病毒血症的血清水平相关联。我们将确定20个人开始抗逆转录病毒治疗（ART）的临床护理设置，并获得HRCT定量和支气管镜样本开始ART之前和之后，以确定ART和病毒血症减少对这些措施的影响。最终，从该应用中获得的信息将有助于理解COPD亚表型发展的潜在机制。此外，这些数据将有助于更好地了解慢性病毒感染（特别是HIV）对COPD易感性的影响。申请人，目前的K12获奖者，已经证明了致力于临床研究的职业生涯。在他职业生涯的早期，他在他正在进行的研究工作中表现出了动力和生产力。该应用程序的结构允许候选人实现他的长期职业目标，成为一名独立的临床研究者，探索改善COPD患者治疗和结局的潜在疗法。在短期内，该提案将允许申请人专门时间进行概述的研究项目，并在与该项目和未来研究计划相关的高级生物统计学和免疫学方面进行教学培训。此外，从本研究提案中生成的数据将构成R 01应用程序的基础。该申请人的研究职业发展计划包括结构化的指导方法，专注于特定研究目标的教学课程， 参加地方和国家会议，确定和定期评估职业里程碑。 由约翰霍普金斯大学提供的研究环境，以及在此应用程序中概述的导师团队将协助候选人的职业生涯和研究目标的成功完成。肺部和重症监护医学部和约翰霍普金斯大学在支持和协作环境中培养成功的临床研究人员方面有着悠久的历史。SHIELD的现有结构，即本申请的伞式项目，将确保研究程序将在本奖项的时间范围内完成。我们已经组建了一支由具有多年生产研究经验和大量先前指导经验的教师组成的指导团队。在与本建议相关的研究领域，每个机构都有独特的、互补的优势。此外，辅导委员会的每一位成员都是申请人职业发展成为独立调查员的优秀榜样。

项目成果

Electronic cigarettes. Potential harms and benefits.

• DOI: 10.1513/annalsats.201311-391fr
• 发表时间: 2014-02-01
• 期刊: Annals of the American Thoracic Society
• 影响因子: 8.3
• 作者: Drummond, M Bradley;Upson, Dona
• 通讯作者: Upson, Dona

Chronic obstructive pulmonary disease: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases.

• DOI: 10.1513/annalsats.201312-432ld
• 发表时间: 2014-04-01
• 期刊: Annals of the American Thoracic Society
• 影响因子: 8.3
• 作者: Drummond, M Bradley;Buist, A Sonia;Rennard, Stephen I
• 通讯作者: Rennard, Stephen I

Risk factors for montelukast treatment failure in step-down therapy for controlled asthma.

• DOI: 10.3109/02770903.2011.627488
• 发表时间: 2011-12
• 期刊: The Journal of asthma : official journal of the Association for the Care of Asthma
• 作者: Drummond MB;Peters SP;Castro M;Holbrook JT;Irvin CG;Smith LJ;Wise RA;Sugar EA;American Lung Association Asthma Clinical Research Center Research Group
• 通讯作者: American Lung Association Asthma Clinical Research Center Research Group

Chronic productive cough is associated with death in smokers with early COPD.

• DOI: 10.3109/15412555.2013.837870
• 发表时间: 2014-08
• 期刊: COPD
• 影响因子: 2.2
• 作者: Putcha N;Drummond MB;Connett JE;Scanlon PD;Tashkin DP;Hansel NN;Wise RA
• 通讯作者: Wise RA

Early chronic obstructive pulmonary disease: definition, assessment, and prevention.

早期慢性阻塞性肺疾病：定义，评估和预防。

• DOI: 10.1016/s0140-6736(15)60647-x
• 发表时间: 2015-05-02
• 期刊: Lancet (London, England)
• 作者: Rennard SI;Drummond MB
• 通讯作者: Drummond MB