Mechanisms of COPD Subphenotype Development

描述(申请人提供)：虽然香烟烟雾暴露与慢性阻塞性肺疾病(COPD)的发展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，香烟烟雾暴露诱导肺内促炎症细胞因子和增加细胞凋亡，导致COPD的呼吸道重塑和以肺气肿为主的亚型。在动物模型中，慢性病毒感染已被证明会增加肺气肿的发生。在这项应用中，我们计划从艾滋病肺部疾病流行病学研究(SHIELD)的一组个体中调查COPD亚型发展的这些潜在机制。Shield是一项正在进行的针对高危或艾滋病毒携带者的队列研究，旨在了解艾滋病毒感染如何影响各种肺部疾病。在这项提案中，我们将进行一项辅助研究，探索慢性病毒感染人群中COPD发展的拟议机制。具体地说，我们将在500名Shield参与者中将肺活量测试中出现的梗阻与高分辨率计算机断层扫描(HRCT)对呼吸道重塑和肺气肿的量化进行关联。我们将评估HIV感染对有梗阻和无梗阻个体的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呼吸道上皮刷检。这些生物样本将被用来检测炎症和凋亡标志物，将其水平与梗阻的存在、呼吸道重塑/肺气肿的HRCT定量以及血清病毒血症水平相关联。我们将在临床护理环境中确定20名开始抗逆转录病毒治疗(ART)的患者，并在开始抗逆转录病毒治疗(ART)前后获取HRCT量化和支气管镜样本，以确定ART和病毒减少对这些措施的影响。最终，从这项应用中获得的信息将有助于理解COPD亚型发展的潜在机制。此外，这些数据将有助于更好地了解慢性病毒感染，特别是艾滋病毒对COPD易感性的影响。申请者，目前的K12获奖者，已经表现出对临床研究事业的奉献精神。在他职业生涯的早期，他在他正在进行的研究努力中表现出了动力和生产力。此应用程序旨在允许应聘者实现其长期的职业目标，即成为一名独立的临床调查员，探索改善COPD患者的治疗和结果的潜在疗法。在当前的时间框架内，这项建议将使申请者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的教学培训。此外，从这项研究提案中产生的数据将构成R01应用的基础。该申请者的研究生涯发展计划包括结构化的指导方法，以特定研究目标为重点的教学课程， 参加地方和国家会议，确定和定期评估职业发展里程碑。 约翰霍普金斯大学提供的研究环境以及本申请表中概述的导师团队将有助于成功完成候选人的职业生涯和研究目标。肺和重症监护医学部和约翰霍普金斯大学在支持和合作环境中培训成功的临床研究人员方面有着悠久的历史。Shield的现有结构是这项申请的总括项目，它将确保在本奖项的时间框架内完成研究程序。我们组建了一支由资深教师组成的指导团队，他们拥有多年的富有成效的研究经验和丰富的先前指导经验。在与这一提议相关的研究领域，每个国家都有不同的、互补的优势。此外，指导委员会的每一名成员都是申请者职业发展成为独立调查员的优秀榜样。 项目简介：该项目旨在了解吸烟导致慢性阻塞性肺疾病(COPD)发展的不同方式。此外，我们还着手确定人类免疫缺陷病毒(HIV)感染如何增加COPD的风险。最终，这些研究应该有助于减少慢性阻塞性肺病和艾滋病毒携带者的疾病和死亡。

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.