Hypercoagulability and Chronic Lung Disease in Older Adults

老年人的高凝状态和慢性肺病

• 批准号: 9764481
• 负责人: Elizabeth Oelsner
• 金额: $ 17.16万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764481
• 关键词: Acute; Adult; Anticoagulants; Asthma; Biological; Biological Testing; Blood; Blood Vessels; Blood flow; CD40 Ligand; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Cohort Studies; Cross-Over Studies; Cross-Sectional Studies; Data; Development; Disease; Elderly; Embolism; Environment; Environmental sludge; Epidemiologist; Epidemiology; Etiology; Event; Factor VIII; Fibrinogen; Funding; General Population; Genetic; Genomics; Genotype; Goals; Hemostatic Agents; Hospitalization; Hypoxemia; Hypoxia; Image; Imaging Techniques; Inflammation; Institutes; Instruction; International; Internist; Longitudinal Studies; Lung; Magnetic Resonance Angiography; Measurement; Measures; Mentors; Mentorship; Methods; Microvascular Dysfunction; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; National Heart, Lung, and Blood Institute; Operations Research; Outcome; Participant; Pathogenesis; Pathway interactions; Patient Recruitments; Patients; Perfusion; Persons; Phase II Clinical Trials; Phenotype; Plasminogen Activator Inhibitor 1; Positioning Attribute; Predictive Factor; Prevention; Prevention therapy; Primary Prevention; Protein C; Protocols documentation; Publications; Publishing; Pulmonary Emphysema; Randomized; Research; Research Personnel; Resources; Respiratory Signs and Symptoms; Respiratory physiology; Risk; Risk Factors; Risk stratification; Role; Sampling; Secondary Prevention; Severities; Smoker; Smoking; Supervision; Surrogate Endpoint; Testing; Thrombomodulin; Thrombophilia; Training; Training Activity; United States National Institutes of Health; Universities; Work; adjudicate; adjudication; apprenticeship; asthma exacerbation; base; career; career development; clinically relevant; cohort; disease diagnosis; disease phenotype; disorder prevention; disorder risk; endothelial dysfunction; experience; follow-up; functional decline; genetic epidemiology; high risk; improved; innovation; instrument; lung imaging; modifiable risk; mortality; multidisciplinary; novel; operation; population based; programs; protein biomarkers; recruit; respiratory; targeted treatment

Project Summary/Abstract Rationale: Chronic lung disease (CLD) is the third leading cause of death in the US. Exacerbations, defined by an increase in respiratory symptoms, are the major driver of morbidity and mortality for the frequently overlapping “obstructive” CLD phenotypes of chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis and asthma. An improved understanding of modifiable risk factors for CLD exacerbations is urgently needed, and – as demonstrated by advances in cardiovascular research – a focus on clinical events may support advances in primary prevention of CLD, a priority for the NHBLI Lung Division. To date, options for risk stratification with respect to incident CLD and exacerbations remain limited in the general population, as the majority of prior CLD studies have studied exacerbations only in persons with established disease. Candidate: The candidate is a general internist at Columbia University (CU) and doctoral candidate in Epidemiology. Building upon her publication on subclinical emphysema in the general population as an independent predictor of all-cause mortality, she has developed a protocol to define and adjudicate CLD events for epidemiologic/primary prevention studies. She is applying this protocol in a six-cohort consortium, which she is currently building to study novel risk factors for CLD events. Her long-term career goal is to develop an independent, cross-disciplinary research program leveraging respiratory epidemiology, genomics and imaging to identify biological pathways that may be targeted in order to achieve primary and secondary prevention of CLD exacerbations. Career Development: The candidate's short-term objectives are to complete her epidemiology doctoral training and to obtain formal training in genomics, individualized instruction in advanced pulmonary imaging techniques, and apprenticeship in the operations of clinical research, while receiving ongoing multidisciplinary mentorship from internationally-recognized leaders in respiratory epidemiology, genomics, magnetic resonance angiography, and clinical research. Environment: CU has abundant resources to support this application including its NIH-CTSA funded Irving Institute for Clinical Research. Research: The proposed research will test biologically plausible hypotheses on how hypercoagulability may represent a biological target for primary and secondary prevention efforts, while also leveraging resources unique to the candidate and providing relevant and career-stage appropriate training to promote her development into an independent investigator. Rates of pulmonary emboli are substantially increased in CLD and exacerbations; nonetheless, the extent to which hypercoagulability is a cause, an effect, or a correlate of CLD is unknown. A causal role for hypercoagulability in CLD is supported by recent findings suggesting that hypoxemia promotes hypercoagulability, that pulmonary perfusion is altered in COPD and exacerbations, and by pilot work from the PI that is highly supportive of the main aims. Aims 1A and 1B will test whether elevated levels of hemostatic factors independently predict incident CLD and incident exacerbations in a case-cohort study nested in the Multi-Ethnic Study of Atherosclerosis (MESA) and a multi- cohort pooled sample developed by the candidate, using methods enriched by the candidate's doctoral training, and cohorts with which she has gained considerable experience working. Aim 1C builds upon her prior experience in genetic epidemiology and proposed genomics training to examine whether genetically estimated hemostatic factors are associated with incident CLD events and longitudinal decline in lung function in the same pooled sample. Clinical endpoints will be classified according to an innovative adjudication protocol developed and validated by the candidate. Confirmation of Aim 1 hypotheses would provide a novel CLD risk score for risk stratification in the general population as well as a biological target for CLD prevention and treatment with anticoagulants. Aim 2 will examine alterations in pulmonary perfusion as a mechanism by which hypercoagulability and sludging may relate to CLD pathogenesis and exacerbations. In Aim 2A, the candidate will coordinate, supervise and analyze pulmonary magnetic resonance angiography (MRA) images for the measurement of pulmonary microvascular blood flow (PMBF), a measure developed by the Mentor and Advisor, during and six weeks following acute CLD exacerbation for 30 participants that she will recruit from an existing cohort. Completion of Aim 2A will reinforce training activities in pulmonary imaging and clinical research operations, and will test the hypotheses that PMBF is acutely diminished in exacerbations compared to baseline; that these differences will persist at six weeks later; and that these changes in PMBF will be correlated with concurrently measured hemostatic factors. In Aim 2B, the candidate will test if hemostatic factors are associated with change in PMBF over five years of follow-up in stable COPD and emphysema. Results from Aim 1 will provide a risk score to support an R01 application on prevention in existing NHLBI cohorts. Aim 2 will provide pilot data to support an R01 on hemostatic factor and pulmonary MRA phenotyping of exacerbations in a larger cohort, and potentially an application for a Phase 2 clinical trial of anticoagulants in persons at high risk for exacerbation, using PMBF as an intermediate phenotype. Hence, completion of the proposed training and scientific aims would position the PI as a respiratory epidemiologist with a unique level of epidemiology, genomics, and imaging training, one or more clinically relevant R01- funded projects, and a commitment to research in primary and secondary prevention of CLD.

项目概要/摘要 理由：慢性肺病 (CLD) 是美国第三大死亡原因，其定义为急性加重。 呼吸道症状的增加是导致发病率和死亡率的主要原因 慢性阻塞性肺疾病 (COPD)、肺气肿、慢性阻塞性肺疾病 (COPD) 的重叠“阻塞性”CLD 表型 对慢性支气管炎和哮喘的可改变危险因素的进一步了解是必要的。 迫切需要，并且正如心血管研究的进展所证明的那样，关注临床事件 可能支持 CLD 一级预防的进展，这是 NHBLI 肺科迄今为止的优先选择。 对于 CLD 的事件风险分层和普通人群中病情恶化的情况仍然有限， 因为大多数先前的 CLD 研究仅对已确诊疾病的人进行了研究。 候选人： 候选人是哥伦比亚大学（CU）的普通内科医生和博士生 流行病学以她关于普通人群亚临床肺气肿的出版物为基础。 作为全因死亡率的独立预测因子，她制定了一项协议来定义和判定 CLD 她正在一个六队列联盟中应用该方案， 她目前正在构建该模型来研究 CLD 事件的新风险因素。她的长期职业目标是 利用呼吸流行病学、基因组学开发独立的跨学科研究项目 和成像来识别可能有针对性的生物途径，以实现主要和次要目标 预防慢性肺病恶化。职业发展：候选人的短期目标是： 完成流行病学博士培训并获得基因组学、个性化指导的正式培训 先进的肺部成像技术和临床研究操作学徒，同时 接受国际公认的呼吸领域领导者的持续多学科指导 流行病学、基因组学、磁共振血管造影和临床研究环境：CU有。 支持该应用的丰富资源，包括 NIH-CTSA 资助的欧文临床研究所 研究：拟议的研究将测试生物学上合理的假设。 高凝状态可能代表一级和二级预防工作的生物学目标，同时也 利用候选人独特的资源，并提供相关的、适合职业阶段的培训 促进她成为一名独立研究者 肺栓塞发生率显着提高。 慢性肺病（CLD）和病情加重的程度增加；然而，高凝状态在一定程度上是原因、结果， 或 CLD 的相关性尚不清楚，最近的研究结果支持 CLD 中高凝状态的因果作用。 表明低氧血症促进高凝状态，肺灌注与慢性阻塞性肺病有关 PI 的试点工作高度支持主要目标 1A 和 1B。 测试凝血因子事件水平升高是否独立预测 CLD 事件和 动脉粥样硬化多种族研究 (MESA) 和多种族研究中的病例队列研究中的恶化 由候选人开发的队列汇总样本，使用候选人博士丰富的方法 她在 Aim 1C 的基础上获得了丰富的工作经验。 先前在遗传流行病学方面的经验，并提出了基因组学培训，以检查遗传是否 估计的止血因素与 CLD 事件和肺功能纵向下降有关 同一汇总样本中的临床终点将根据创新裁决进行分类。 由候选者开发和验证的协议将提供一种新颖的目标 1 假设的确认。 用于一般人群风险分层的 CLD 风险评分以及 CLD 预防的生物学目标 目标 2 将检查肺灌注的变化作为一种​​机制。 在目标 2A 中，高凝状态和淤积可能与 CLD 发病机制和恶化有关。 候选人将协调、监督和分析肺磁共振血管造影（MRA）图像 用于测量肺微血管血流量 (PMBF)，这是由 Mentor 和 顾问，在 CLD 急性加重期间和之后六周，她将从一个机构招募 30 名参与者 目标 2A 的完成将加强肺部成像和临床方面的培训活动。 研究操作，并将检验以下假设：与 到基线；这些差异将在六周后持续存在，并且 PMBF 的这些变化将是 与同时测量的止血因素相关。在目标 2B 中，考生将测试是否具有止血作用。 稳定期慢性阻塞性肺病和肺气肿五年随访中的因素与 PMBF 变化相关。 目标 1 的结果将提供风险评分，以支持现有 NHLBI 中预防的 R01 应用 目标 2 将提供试点数据来支持止血因子和肺部 MRA 表型分析的 R01。 更大队列中的病情加重，并有可能申请抗凝剂的 2 期临床试验 急性加重风险高的人，使用 PMBF 作为中间表型因此，完成了。 拟议的培训和科学目标将使 PI 成为一名呼吸道流行病学家，具有 独特水平的流行病学、基因组学和影像学培训，一项或多项临床相关的 R01- 资助的项目，以及对慢性肺病一级和二级预防研究的承诺。