The Pulmonary Vasculature and Platelets in Emphysema and COPD

依据：慢性阻塞性肺疾病（COPD）和肺气肿是 慢性下呼吸道疾病是美国和世界第四大死因。尽管 因此，没有针对COPD的疾病改善药理学疗法。因此，有机会 通过识别和测试改变疾病进展的生物疗法来推进COPD的治疗。 候选人：作为布里格姆妇女医院接受过肺重症监护培训的医生和讲师 (BWH)和哈佛医学院（HMS），PI已经进行了初步研究， 活化是COPD和肺气肿的潜在危险因素。PI的长期目标是成为一名 独立的临床研究者，专注于影响发展和进展的策略 肺气肿和COPD。职业发展：PI的短期目标是完成硕士学位， 流行病学，了解成像分析，血小板活化和临床试验设计的措施， 她将在已组建的多学科指导小组的指导下开展业务。 环境：BWH和HMS在研究职业发展方面取得了成功， 承诺投入大量资源来支持这一提案，包括使用BWH临床中心 调查研究：拟议的研究目标将评估肺气肿的血管假说， 一个特定的相关生物途径（血小板活化）的连续步骤。目标1将评估关联 肺血管形态和CT上肺气肿百分比的进展之间的关系。目标2将 在1，537例样本中测量尿11-脱氢-血栓烷B2，体内血小板活化的测量 COPD研究（SPIROMICS）中测量的亚群和中间结局的参与者， 血小板活化是否与肺气肿和肺血管形态学相关， 截面分析，以及它是否预测肺气肿的纵向进展。目标3将招募20名小说 参与者的CT检查可见肺气肿和轻中度COPD的交叉研究，以确定 双重抗血小板治疗是否改善双能CT扫描的肺微血管灌注 与安慰剂相比。总之，这些目标将肺血管、血小板活化和肺气肿联系起来 进展，并将测试是否抑制血小板活化影响我们的微血管的措施， 肺灌注双重抗血小板治疗肺灌注的改善提示， 这些治疗可能会影响肺气肿的长期进展，我建议在一个实验室中测试这一假设。 未来R 01/IIb期RCT。在完成这些研究目标的过程中，PI旨在确定一种潜在的新颖性 与肺气肿和COPD相关的途径，并获得专业知识，以建立一个独立的研究 该计划旨在识别和测试影响肺气肿和COPD进展的疗法。

Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are the major components of chronic lower respiratory disease, the 4th leading cause of death in the United States and the world. Despite this, there are no disease-modifying pharmacologic therapies for COPD. Thus, there are opportunities to advance treatment of COPD by identifying and testing biological therapies that alter disease progression. Candidate: As a pulmonary-critical care-trained physician and Instructor at Brigham and Women's Hospital (BWH) and Harvard Medical School (HMS), the PI has conducted preliminary research identifying platelet activation as a potential risk factor for COPD and emphysema. The PI's long term goal is to become an independent clinical investigator with a focus on strategies that impact the development and progression of emphysema and COPD. Career Development: The PI's short term goals are to complete a Master's Degree in Epidemiology, to learn about imaging analysis, measures of platelet activation and clinical trial design and operations, which she will do with the guidance of the assembled multi-disciplinary mentorship team. Environment: BWH and HMS have a track-record of success in research career development and has committed significant resources to support this proposal including use of the BWH Center for Clinical Investigation. Research: The proposed research aims will evaluate the vascular hypothesis of emphysema and a specific related biological pathway (platelet activation) in sequential steps. Aim 1 will assess the association between pulmonary vascular morphology and the progression of percent emphysema on CT. Aim 2 will measure urinary 11-dehydro-thromboxane B2, a measure of in vivo platelet activation, in a sample of 1,537 participants in the Subpopulations and Intermediate Outcomes Measured in COPD Study (SPIROMICS) to test whether platelet activation is associated with emphysema and pulmonary vascular morphology in cross- sectional analyses, and whether it predicts longitudinal progression of emphysema. Aim 3 will recruit 20 novel participants with visual emphysema on CT and mild-moderate COPD for a crossover study to determine whether dual antiplatelet therapy improves pulmonary microvascular perfusion on dual-energy CT scan compared to placebo. Together, these aims link the pulmonary vasculature, platelet activation and emphysema progression, and will test whether inhibiting platelet activation impacts our measures of microvascular pulmonary perfusion. Improvement in pulmonary perfusion with dual antiplatelet therapy would suggest that these therapies may impact long-term progression of emphysema, a hypothesis I would propose to test in a future R01/phase IIb RCT. In completing these research objectives, the PI aims to identify a potential novel pathway related to emphysema and COPD, and gain the expertise to establish an independent research program that identifies and tests therapies that impact the progression of emphysema and COPD.