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

• 批准号: 10356832
• 负责人: Ashraf Fawzy
• 金额: $ 19.76万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/10356832
• 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; Lead; Leukocyte Trafficking; Leukocytes; Link; Measures; Membrane; Mentorship; Methodology; Morbidity - disease rate; Observational Study; Outcome; P-Selectin; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Platelet Activation; Platelet Count measurement; Play; Population; Primary Prevention; Procedures; Process; Proteins; Quality of life; Randomized; Randomized Controlled Trials; 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; Time; 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

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.

项目总结/摘要 慢性阻塞性肺疾病（COPD）是美国第四大死亡原因。 目前，COPD的治疗依赖于吸入器疗法的逐步算法，而不靶向全身性给药。 流程.越来越多的证据表明，活化血小板可能在COPD中发挥作用，但其机制 血小板活化对COPD预后的影响尚不清楚。此外，很难 区分COPD和心血管疾病（CVD）以来的呼吸事件和心血管症状 是高度共病的了解血小板在COPD中的作用和靶向抗血小板治疗的潜力 没有CVD的患者可能导致新的治疗选择。既往研究表明 血小板活化与COPD患者呼吸系统发病率之间的关系采用了非特异性替代物 生物标志物。同样，先前的研究显示阿司匹林的使用与COPD发病率的改善有关， 在易受选择偏倚影响的观察队列中， 因适应症而混淆。为了了解特异性血小板活化途径在血小板活化中的潜在作用， 在COPD的呼吸道发病率，我们建议直接测量血小板活化和反应性的样本， 115例COPD患者，无明显或亚临床CVD（通过无冠状动脉确定） CT扫描显示钙化具体来说，我们将测量膜受体独特的 表达于活化血小板（CD 62 P/P-选择素、CD 63、CD 154/CD 4L和PAC 1）、血小板-白细胞 缀合物（血小板-单核细胞和血小板-中性粒细胞缀合物）和血小板应答（即， 激活）与三种激动剂（二磷酸腺苷、血栓素和5-羟色胺）的刺激。我们 假设基线循环活化血小板比例越高， 白细胞结合物和血小板对低剂量激动剂的反应性增加将与 基线呼吸道症状更严重，生活质量更差，COPD急性加重率更高 超过1年。此外，我们将进行一项随机双盲顺序交叉研究， 在48名COPD患者中，没有CVD，以确定最有效的阿司匹林剂量， 抑制血小板活化和反应性。完成拟议目标将阐明 血小板活化和反应性通路在COPD呼吸结局中的作用，并为设计 一项规模更大的COPD抗血小板治疗随机对照试验。我们将从大量的 参与约翰霍普金斯正在进行和已完成的COPD研究， 约翰霍普金斯COPD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，专注于确定个性化治疗的新靶点， 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 培养COPD内定型、转化研究、血小板生物学和临床试验设计方面的新技能。