Platelet Activation Pathways and Respiratory Morbidity in COPD

慢性阻塞性肺病 (COPD) 中的血小板激活途径和呼吸系统发病率

基本信息

批准号：
10577872
负责人：
Ashraf Fawzy
金额：
$ 19.71万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-20 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577872
关键词：
Acute Adenosine Diphosphate Adrenal Cortex Hormones Agonist Algorithms Arachidonic Acids Aspirin Biological Markers Biology Blood Platelets Bronchodilator Agents Cardiovascular Diseases Cardiovascular system Cause of Death Cell physiology Cells Chronic Obstructive Pulmonary Disease Clinical Trials Clinical Trials Design Collagen Cross-Over Studies Data Development Development Plans Disease Disease Outcome Dose Double-Blind Method Emergency department visit Endothelium Event Future Goals Hospitalization Immune In Vitro Incidence Individual Inflammation Infrastructure Inhalation Inhalators Laboratories Leukocyte Trafficking Leukocytes Link Measures Membrane Mentorship Methodology Morbidity - disease rate Observational Study Outcome Participant Pathway interactions Patients Pharmaceutical Preparations Platelet Activation Platelet Count measurement Population Predisposition Primary Prevention Procedures Process Proteins Quality of life Randomized Randomized, Controlled Trials Recommendation Respiratory Disease Respiratory Signs and Symptoms Role SELP gene Sampling Scanning Selection Bias Serotonin Severity of illness Smoker Surrogate Markers Symptoms Systemic Therapy TNFSF5 gene Telephone Thromboxane B2 Thromboxanes Training Translational Research United States Work X-Ray Computed Tomography atherosclerotic plaque rupture cardiovascular disorder prevention career career development circulating biomarkers cohort comorbidity coronary artery calcification design diabetic digital repositories epidemiology study experience follow-up former smoker improved in vivo individualized medicine monocyte mortality neutrophil novel novel therapeutics precision medicine prospective pulmonary function randomized trial receptor recruit respiratory respiratory morbidity response skills systemic inflammatory response trafficking translational scientist urinary

项目摘要

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.

项目概要/摘要慢性阻塞性肺疾病（COPD）是美国第四大死因。目前，慢性阻塞性肺病的治疗依赖于吸入疗法的逐步算法，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病中发挥作用，但其机制血小板活化对慢性阻塞性肺病结局的影响尚不清楚。此外，已经很难区分慢性阻塞性肺病 (COPD) 和心血管疾病 (CVD) 后的呼吸事件与心血管症状是高度共病的。了解血小板的作用以及慢性阻塞性肺病靶向抗血小板治疗的潜力没有 CVD 的患者可能会带来新的治疗选择。先前的研究表明存在关联血小板活化与慢性阻塞性肺病 (COPD) 中更严重的呼吸系统疾病发病率之间的关系采用了非特异性替代指标生物标志物。同样，先前的研究表明阿司匹林的使用与慢性阻塞性肺病发病率的改善有关死亡率是观察队列中普遍存在的用户，容易受到选择偏差的影响通过指示混淆。为了了解特定血小板激活途径的潜在作用为了了解慢性阻塞性肺病 (COPD) 的呼吸系统发病率，我们建议直接测量样本中的血小板活化和反应性 115 名患有慢性阻塞性肺病 (COPD) 的个体，根据冠状动脉缺失确定，没有明显或亚临床心血管疾病 (CVD) 计算机断层扫描显示钙化。具体来说，我们将独特地测量膜受体在活化血小板（CD62P/P-选择素、CD63、CD154/CD4L 和 PAC1）、血小板白细胞上表达缀合物（血小板-单核细胞和血小板-中性粒细胞缀合物）和血小板反应（即变化激活）到用三种激动剂（二磷酸腺苷、血栓素和血清素）进行刺激。我们假设基线循环活化血小板的比例较高，血小板- 白细胞缀合物和响应低剂量激动剂的血小板反应性增加将相关基线呼吸道症状较高，生活质量较差，慢性阻塞性肺病急性加重率较高 1年多。此外，我们将对三项研究进行随机双盲序贯交叉研究对 48 名没有 CVD 的 COPD 患者进行阿司匹林剂量测定，以确定最有效的阿司匹林剂量抑制该人群中的血小板活化和反应性。完成拟议目标将阐明血小板活化和反应途径对 COPD 呼吸结局的作用，并为设计提供信息一项针对慢性阻塞性肺病抗血小板治疗的大型随机对照试验。我们将从大量人才中招募约翰霍普金斯大学正在进行和已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大学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转化研究者，专注于确定个体化治疗的新靶点慢性阻塞性肺病。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 内分型、转化研究、血小板生物学和临床试验设计方面的新技能。