Mechanisms of COPD Subphenotype Development

描述（由申请人提供）：虽然香烟烟雾暴露与慢性阻塞性肺疾病（COPD）发展之间的因果关系已经牢固确立，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，香烟烟雾暴露可诱导促炎细胞因子和肺内细胞凋亡增加，导致气道重塑和肺气肿- COPD的主要亚表型。在动物模型中，慢性病毒感染已被证明可以增加肺气肿的发展。在这项应用中，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是一项正在进行的针对高危人群或HIV感染者的队列研究，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发展的机制。具体而言，我们将在500名SHIELD参与者中，将肺量测定中存在的阻塞与气道重塑和肺气肿的高分辨率计算机断层扫描（HRCT）量化相关联。我们将评估HIV感染对有和无梗阻个体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洗。这些生物样本将用于检测炎症和凋亡标志物，将其水平与阻塞、气道重塑/肺气肿的HRCT量化和病毒血症的血清水平联系起来。我们将确定在临床护理中开始抗逆转录病毒治疗（ART）的20名患者，并在开始抗逆转录病毒治疗前后获得HRCT定量和支气管镜样本，以确定抗逆转录病毒治疗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。申请人目前是K12奖获得者，在临床研究方面表现出了奉献精神。在他的职业生涯早期，他在他正在进行的研究工作中表现出了动力和生产力。该申请旨在使候选人实现其长期职业目标，即成为一名独立的临床研究者，探索改善COPD患者治疗和预后的潜在疗法。在短期内，该提案将允许申请人有专门的时间进行概述的研究项目，并进行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教学培训。此外，本研究计划产生的数据将构成R01申请的基础。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，

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. Project Narrative: This project seeks to understand the different ways that cigarette smoke leads to the development of chronic obstructive pulmonary disease (COPD). As well, we set out to determine how human immunodeficiency virus (HIV) infection increases the risk of COPD. Ultimately, these studies should help reduce illness and death among those with COPD and HIV.