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.

项目摘要/摘要 理由：慢性肺病(CLD)是美国第三大死因。加重，定义为 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、 慢性支气管炎和哮喘。对慢性阻塞性肺疾病恶化的可修改危险因素的更好理解是 迫切需要，而且--心血管研究的进展表明--对临床事件的关注 可支持在慢性肺病一级预防方面取得进展，这是NHBLI肺科的优先事项。到目前为止，选项 在普通人群中，与CLD事件和病情恶化有关的风险分层仍然有限， 因为之前的大多数CLD研究只研究了有既往疾病的人的病情恶化。 候选人：应聘者是哥伦比亚大学(CU)的普通内科医生，同时也是 流行病学。基于她发表的关于普通人群中亚临床肺气肿的文章 作为全因死亡率的独立预测者，她开发了一种方案来定义和判定CLD 流行病学/初级预防研究的活动。她正在一个由六个人组成的财团中应用这一方案， 她目前正在建立该实验室，以研究CLD事件的新风险因素。她的长期职业目标是 开发独立的跨学科研究计划，利用呼吸道流行病学、基因组学 和成像，以确定可能被靶向的生物途径，以实现初级和次级 预防慢性阻塞性肺疾病的恶化。职业发展：应聘者的短期目标是 完成她的流行病学博士培训，并获得正式的基因组学培训，个性化指导 在先进的肺部成像技术和见习手术的临床研究，而 从国际公认的呼吸系统领导者那里获得持续的多学科指导 流行病学、基因组学、磁共振血管成像和临床研究。环境：CU有 支持这一申请的充足资源，包括其由NIH-CTSA资助的欧文临床研究所 研究。研究：这项拟议的研究将检验生物学上可信的假说 高凝状态可能是一级和二级预防工作的生物目标，同时也 利用候选人独有的资源，并提供相关和职业阶段的适当培训，以 促进她成为一名独立的调查员。肺栓子的发生率基本上是 慢性阻塞性肺疾病和病情恶化的增加；然而，高凝状态是一个原因，一个结果， 或者，CLD的相关性尚不清楚。最近的发现支持慢性阻塞性肺疾病高凝状态的原因 提示低氧血症促进高凝状态，慢性阻塞性肺疾病和慢性阻塞性肺疾病患者肺灌注改变。 国际和平研究所的试点工作对主要目标给予了高度支持。目标A和1B将 检测止血因子水平升高是否独立预测CLD事件和事件 一项嵌套在动脉粥样硬化多种族研究(MESA)和一项多种族研究的病例队列研究中的恶化 由候选人开发的队列汇集样本，使用由候选人的博士丰富的方法 培训，以及她与之合作获得了相当多工作经验的同龄人。AIM 1C建立在她的基础上 以前有遗传流行病学经验，并建议进行基因组学培训，以检查基因是否 估计的止血因素与CLD事件和肺功能纵向下降有关 在相同的混合样本中。临床终点将根据创新的裁决进行分类 由应聘者制定和验证的协议。对目标1假设的确认将提供一种新的 用于普通人群风险分层的CLD风险评分以及用于CLD预防的生物学指标 并使用抗凝剂进行治疗。Aim 2将检查肺血流灌注的变化，作为一种机制 其中高凝状态和淤泥状态可能与CLD的发病和加重有关。在Aim 2a中， 负责协调、监督和分析肺磁共振血管成像(MRA)图像 对于肺微血管血流量(PMBF)的测量，这是由Mentor和 顾问，在CLD急性加重期间和之后的六周内，她将从 现有的队列。Aim 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PMBF在恶化中显著减少的假设 这些差异将持续到六周后；PMBF的这些变化将是 与同时测量的止血因子相关。在目标2B中，候选人将测试止血是否 这些因素与稳定期COPD和肺气肿患者五年随访期间PMBF的变化有关。 AIM 1的结果将提供风险评分，以支持R01在现有NHLBI中的预防应用 一群人。AIM 2将提供试点数据，以支持关于止血因子和肺MRA表型的R01 在更大的队列中恶化的可能性，并可能申请在中国进行抗凝剂的第二阶段临床试验 病情恶化的高危人群，使用PMBF作为中间表型。因此，完成 拟议的培训和科学目标将使PI成为一名呼吸流行病学家 独特的流行病学、基因组学和成像培训水平，一个或多个临床相关的R01- 资助的项目，以及致力于慢性阻塞性肺病一级和二级预防的研究。