Hypercoagulability and Chronic Lung Disease in Older Adults

老年人的高凝状态和慢性肺病

• 批准号: 9180241
• 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/9180241
• 关键词: Acute; Adult; Anticoagulants; Asthma; Atherosclerosis; Biological; Biological Markers; 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; Internist; Longitudinal Studies; Lung; Magnetic Resonance Angiography; Measurement; Measures; Mentors; Mentorship; Methods; Microvascular Dysfunction; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Operations Research; Outcome; Participant; Pathogenesis; Pathway interactions; Patients; Perfusion; Persons; Phase II Clinical Trials; Phenotype; Plasminogen Activator Inhibitor 1; Positioning Attribute; Prevention; Prevention therapy; Primary Prevention; Protein C; Protocols documentation; Publications; Publishing; Pulmonary Emphysema; Randomized; Recruitment Activity; Research; Research Personnel; Resources; Respiratory Signs and Symptoms; Respiratory physiology; Risk; Risk Factors; Role; Sampling; Secondary Prevention; Severities; Smoker; Smoking; Staging; Stratification; Surrogate Endpoint; Testing; Thrombomodulin; Thrombophilia; Training; Training Activity; United States National Institutes of Health; Universities; Work; abstracting; adjudicate; adjudication; apprenticeship; base; career; career development; clinically relevant; cohort; disease diagnosis; disease phenotype; disorder prevention; disorder risk; endothelial dysfunction; experience; follow-up; genetic epidemiology; high risk; improved; innovation; instrument; lung imaging; modifiable risk; mortality; multidisciplinary; novel; operation; population based; programs; 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.

项目总结/摘要 依据：慢性肺病（CLD）是美国第三大死亡原因。急性加重，定义为 呼吸道症状的增加，是发病率和死亡率的主要驱动因素， 慢性阻塞性肺病（COPD），肺气肿， 慢性支气管炎和哮喘。对CLD急性加重的可改变风险因素的进一步理解是 心血管研究的进展表明，迫切需要关注临床事件 可能支持CLD一级预防的进展，这是NHBLI肺部分部的优先事项。迄今为止， 关于CLD事件和加重的风险分层在一般人群中仍然有限， 因为大多数先前的CLD研究仅在已确诊疾病的患者中研究了急性加重。 候选人：候选人是哥伦比亚大学（CU）的普通内科医生， 流行病学。基于她发表的关于一般人群亚临床肺气肿的文章， 作为全因死亡率的独立预测因子，她制定了一项定义和判定CLD的方案 流行病学/一级预防研究。她正在一个六组的联合体中应用这个方案， 她目前正在构建该模型，以研究CLD事件的新风险因素。她的长期职业目标是 开发一个独立的，跨学科的研究计划，利用呼吸流行病学，基因组学 和成像，以确定可能成为目标的生物途径，以实现初级和次级 预防CLD恶化。职业发展：候选人的短期目标是 完成她的流行病学博士培训，并获得基因组学，个性化指导的正式培训 在先进的肺部成像技术，并在临床研究的操作学徒，而 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 丰富的资源来支持这一应用，包括其NIH-CTSA资助的欧文临床研究所 Research.研究：拟议的研究将测试生物学上合理的假设， 高凝状态可能是一级和二级预防工作的生物学目标，同时也是 利用候选人独有的资源，并提供相关的职业阶段适当的培训， 让她成长为一名独立调查员肺栓塞的发生率 CLD和急性加重增加;尽管如此，高凝状态是原因，影响， 或CLD的相关性未知。最近的研究结果支持高凝状态在CLD中的因果作用 表明低氧血症促进高凝状态，COPD患者的肺灌注改变， 急性加重，并通过PI的试点工作，这是高度支持的主要目标。目标1A和1B将 测试止血因子水平升高是否独立预测CLD事件和CLD事件 一项嵌套在多种族动脉粥样硬化研究（梅萨）中的病例队列研究和一项多种族 由候选人开发的队列合并样本，使用候选人的博士生丰富的方法 培训，并与她获得了相当多的工作经验的同伙。目标1C建立在她的基础上 先前在遗传流行病学方面的经验，并建议进行基因组学培训，以检查基因 估计的止血因子与CLD事件和肺功能纵向下降相关 在同一个样本中。将根据创新裁定对临床终点进行分类 由候选人制定和验证的方案。目标1假设的确认将提供一种新的 用于一般人群风险分层的CLD风险评分以及CLD预防的生物学靶点 和抗凝剂治疗。目的2将通过以下方法研究肺灌注的改变作为一种机制： 高凝状态和淤积可能与CLD的发病和加重有关。在目标2A中， 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Mentor开发的一种测量方法， 顾问，在CLD急性加重期间和之后6周，她将从一个 现有的cohort。目标2A的完成将加强肺部成像和临床 研究操作，并将测试以下假设，即与对照组相比， 这些差异将在6周后持续存在;并且这些PMBF的变化将 与同时测量的止血因子相关。在目标2B中，候选人将测试是否止血 这些因素与稳定期COPD和肺气肿患者5年随访期间PMBF的变化相关。 Aim 1的结果将提供风险评分，以支持现有NHLBI中预防的R 01应用 同伙目的2将提供初步数据，以支持止血因子和肺部MRA表型的R 01 在更大的队列中急性加重，并可能应用于抗凝剂的2期临床试验， 急性加重高危人群，使用PMBF作为中间表型。因此， 拟议的培训和科学目标将PI定位为呼吸流行病学家， 独特水平的流行病学、基因组学和成像培训，一个或多个临床相关R 01- 资助的项目，并致力于慢性肺病的初级和二级预防研究。