Mechanisms of COPD Subphenotype Development

COPD 亚表型发展机制

• 批准号: 8110017
• 负责人: Michael Bradley Drummond
• 金额: $ 16.27万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110017
• 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. 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.

描述（由申请人提供）：虽然香烟烟雾暴露与慢性阻塞性肺病（COPD）发展之间的因果关系已被牢固确立，但人类肺病不同易感性和表现的潜在机制仍不清楚。实验模型表明，香烟烟雾暴露会诱导促炎细胞因子并增加肺内细胞凋亡，导致气道重塑和慢性阻塞性肺病的肺气肿亚表型。在动物模型中，慢性病毒感染已被证明会加剧肺气肿的发展。在此应用中，我们计划在肺部疾病 HIV 流行病学研究 (SHIELD) 的一组个体中研究 COPD 亚表型发展的潜在机制。 SHIELD 是一项针对高危人群或艾滋病毒感染者正在进行的队列研究，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慢性阻塞性肺病（COPD）发展的拟议机制。具体来说，我们将 500 名 SHIELD 参与者的肺量测定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) 量化相关联。我们将评估 HIV 感染对有或无梗阻个体 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液和气道上皮刷洗结果。这些生物样本将用于测定炎症和细胞凋亡标记物，将其水平与阻塞的存在、气道重塑/肺气肿的 HRCT 定量以及病毒血症的血清水平相关联。我们将确定 20 名在临床护理中开始抗逆转录病毒治疗 (ART) 的个体，并在开始 ART 之前和之后获取 HRCT 定量和支气管镜样本，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（特别是艾滋病毒）对慢性阻塞性肺病（COPD）易感性的影响。申请人是当前 K12 获奖者，表现出了对临床研究职业的奉献精神。在他的职业生涯早期，他在正在进行的研究工作中表现出了积极性和生产力。该应用程序的结构是为了让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，探索改善慢性阻塞性肺病患者治疗和结果的潜在疗法。在当前的时间范围内，该提案将允许申请人投入时间来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，本研究提案生成的数据将构成 R01 应用的基础。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。 约翰霍普金斯大学提供的研究环境以及本申请中概述的导师团队将有助于候选人成功完成职业和研究目标。肺科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（该申请的伞式项目）将确保研究程序将在该奖项的期限内完成。我们组建了一支由资深教师组成的指导团队，他们拥有多年富有成效的研究经验和丰富的先前指导经验。每个人在与本提案相关的研究领域都有独特的、互补的优势。此外，指导委员会的每位成员都为申请人的职业发展成为独立研究者提供了优秀的榜样。 项目叙述：该项目旨在了解香烟烟雾导致慢性阻塞性肺病 (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) 感染如何增加慢性阻塞性肺病 (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患者的疾病和死亡。