The Pulmonary Vasculature and Platelets in Emphysema and COPD

理论基础：慢性阻塞性肺疾病(COPD)和肺气肿是 慢性下呼吸道疾病，美国和世界第四大死因。尽管 因此，目前还没有治疗慢性阻塞性肺疾病的药物疗法。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。 应聘者：在布里格姆妇女医院接受过肺部危重护理培训的医生和讲师 (BWH)和哈佛医学院(HMS)，PI已经进行了初步研究，确定了血小板 激活是慢性阻塞性肺疾病和肺气肿的潜在危险因素。PI的长期目标是成为一名 独立的临床研究员，专注于影响疾病发展和进展的策略 肺气肿和慢性阻塞性肺病。职业发展：私人助理的短期目标是在 流行病学，以了解成像分析，血小板激活的测量和临床试验设计和 她将在组建的多学科指导团队的指导下进行这项工作。 环境：BWH和HMS在研究职业发展方面有成功的记录，并 投入大量资源支持这项提议，包括使用BWH临床中心 调查。研究：建议的研究目标将评估肺气肿的血管假说和 一种特定的相关生物途径(血小板激活)，按顺序进行。目标1将评估该协会 肺血管形态与CT上肺气肿百分比进展的关系。目标2将 在1,537名样本中检测尿中11-脱氢血栓素B2，这是一种体内血小板活化的指标 在COPD研究中测量的亚群和中间结果的参与者(SPIROMICS)进行测试 血小板活化是否与肺气肿和肺血管形态有关 横断面分析，以及它是否可以预测肺气肿的纵向进展。《目标3》将征集20部小说 对CT上有视觉肺气肿和轻中度COPD的参与者进行交叉研究，以确定 双能CT扫描双抗血小板治疗是否改善肺微血管血流灌注 与安慰剂相比。这些目标共同将肺血管系统、血小板活化和肺气肿联系在一起。 进展，并将测试抑制血小板激活是否影响我们的微血管测量 肺血流灌注。双重抗血小板治疗可改善肺血流灌注 这些疗法可能会影响肺气肿的长期进展，我建议在一项 未来R01/IIb阶段RCT。在完成这些研究目标的过程中，PI的目标是确定一部潜在的小说 与肺气肿和慢性阻塞性肺病相关的途径，并获得建立独立研究的专业知识 识别和测试影响肺气肿和慢性阻塞性肺病进展的治疗方法的计划。

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.