Platelet Activation Pathways and Respiratory Morbidity in COPD

项目摘要/摘要 慢性阻塞性肺疾病(COPD)是美国第四大死因。 目前，COPD的治疗依赖于吸入器疗法的逐步算法，而不是针对全身 流程。越来越多的证据表明，活化的血小板可能在慢性阻塞性肺疾病中发挥作用，但其机制 而血小板激活对COPD预后的影响尚不清楚。此外，很难做到 从慢性阻塞性肺疾病和心血管疾病(CVD)开始区分呼吸事件和心血管症状 是高度并存的。了解血小板在慢性阻塞性肺疾病中的作用和靶向抗血小板治疗的潜力 没有心血管疾病的患者可能会带来新的治疗选择。先前的研究表明两者之间存在关联 慢性阻塞性肺疾病患者的血小板活化与更严重的呼吸道并发症之间的关系采用了非特异性替代物 生物标志物。同样，先前的研究表明使用阿司匹林与改善COPD发病率和 死亡率在观察队列中普遍存在，容易受到选择偏差和 有迹象表明令人困惑。为了了解特定的血小板活化途径在血小板活化中的潜在作用 COPD的呼吸道发病率，我们建议在一个样本中直接测量血小板的活化和反应性 115例因冠状动脉缺失而无显性或亚临床心血管疾病的COPD患者 计算机断层扫描显示有钙化。具体地说，我们将独特地测量膜受体 表达于活化的血小板(CD62P/P-选择素、CD63、CD154/CD4L和PAC1)、血小板-白细胞 结合物(血小板-单核细胞和血小板-中性粒细胞结合物)和血小板反应(即 激活)对三种激动剂(二磷酸腺苷、血栓素和5-羟色胺)的刺激。我们 假设更高比例的基线循环激活的血小板，更高比例的血小板- 白细胞结合和对低剂量激动剂反应的血小板反应性增加将是相关的 基线呼吸道症状越高，生活质量越差，COPD急性加重率越高 一年以上。此外，我们将进行随机、双盲、序贯交叉研究 48例无心血管疾病的慢性阻塞性肺疾病患者的阿司匹林剂量 抑制这一人群中的血小板活化和反应性。拟议目标的完成将澄清 血小板活化和反应途径在COPD患者呼吸结局中的作用 一项更大规模的COPD抗血小板治疗随机对照试验。我们将从庞大的人才库中招聘 约翰霍普金斯大学正在进行和完成的慢性阻塞性肺病研究的参与者，通过利用 约翰霍普金斯慢性阻塞性肺病精准医学卓越中心的基础设施。我的最终职业目标是 成为一名独立的翻译研究人员，专注于寻找个性化治疗的新靶点 慢性阻塞性肺疾病（慢阻肺）。我的职业发展计划包括专家指导、正式课程和实践经验 开发COPD内切分型、转译研究、血小板生物学和临床试验设计方面的新技能。

PROJECT SUMMARY / ABSTRACT Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States. Currently, the treatment of COPD relies on a stepwise algorithm of inhaler therapies without targeting systemic processes. Mounting evidence suggests that activated platelets may play a role in COPD but the mechanisms and impact of platelet activation on COPD outcomes are not known. Furthermore, it has been difficult to differentiate respiratory events from cardiovascular symptoms since COPD and cardiovascular disease (CVD) are highly comorbid. Understanding the role of platelets and potential for targeted antiplatelet therapy in COPD patients without CVD could lead to novel therapeutic options. Prior studies demonstrating an association between platelet activation and worse respiratory morbidity in COPD have employed non-specific surrogate biomarkers. Likewise, prior studies showing an association of aspirin use with improved COPD morbidity and mortality have been among prevalent users in observational cohorts susceptible to selection bias and confounding by indication. In order to understand the potential role of specific platelet activation pathways on respiratory morbidity in COPD, we propose directly measuring platelet activation and reactivity in a sample of 115 individuals with COPD without overt or subclinical CVD as determined by absence of coronary artery calcification on computed tomography scan. Specifically, we will measure membrane receptors uniquely expressed on activated platelets (CD62P/P-selectin, CD63, CD154/CD4L, and PAC1), platelet-leukocyte conjugates (platelet-monocyte and platelet-neutrophil conjugates), and platelet response (i.e. change in activation) to stimulation with three agonists (adenosine diphosphate, thromboxane, and serotonin). We hypothesize that higher proportion of baseline circulating activated platelets, higher proportion of platelet- leukocyte conjugates, and increased platelet reactivity in response to low doses of agonists will be associated with higher baseline respiratory symptoms, worse quality of life and higher rate of acute exacerbations of COPD over 1 year. Furthermore, we will conduct a randomized double-blinded sequential crossover study of three aspirin doses in 48 individuals with COPD without CVD to determine the most effective aspirin dose for suppression of platelet activation and reactivity in this population. Completion of the proposed aims will elucidate the role of platelet activation and reactivity pathways on respiratory outcomes in COPD and inform the design of a larger randomized controlled trial of antiplatelet therapy in COPD. We will recruit from the large pool of participants in ongoing and completed COPD studies at Johns Hopkins supplemented by leveraging the infrastructure of the Johns Hopkins COPD Precision Medicine Center of Excellence. My ultimate career goal is to be an independent translational researcher focusing on identifying novel targets for individualized therapy in COPD. My career development plan includes expert mentorship, formal coursework, and hands-on experience to develop new skills in COPD endotyping, translational research, platelet biology, and clinical trial design.