Leveraging Serum Metabolomics to Understand Clinical Phenotypes in COPD

项目概要/摘要 慢性阻塞性肺疾病（COPD）是普遍的、昂贵的并且与高发病率和高并发症相关。 mortality.它也是一个显着的异质性条件方面，其肺部和全身 表现。这种异质性的机制基础仍然知之甚少， COPD患者的治疗方法基本相同。代谢组学是一门大规模研究低浓度代谢产物的学科。 分子量化合物，通常称为代谢物，在细胞、组织或生物体液中。 初步数据表明，特定的代谢组学特征与不良的临床结局相关， 可能揭示疾病异质性的独特见解。这些调查最终可能导致 迫切需要的新的治疗方法的发展。然而， 代谢组学在COPD中仍然很大程度上未被开发。此K23辅导职业发展应用 提出了一个协调的5年培训和研究计划，让Wassim Labaki，MD，MS实现他的 成为一名独立的医学科学家的长期目标。他的科学重点将是以病人为导向 临床和转化COPD研究，特别是在代谢组学领域。拉巴基博士将接受 他不仅得到了代谢组学专家的建议，还得到了生物信息学和临床研究专家的建议， 在获奖期间磨练这些技能。他的培训计划将包括在大学的高级课程 密歇根大学公共卫生学院和计算医学与生物信息学系， 在密歇根大学代谢组学实验室的实践经验的补充 并定期参加各种国家和机构讲习班和会议。此应用程序将 利用临床特征良好的NIH资助的SPIROMICS COPD队列， 参与COPD发病机制和进展的机械代谢途径，可进行干预 在病程的早期。本课题的具体目标是：1）明确血清代谢组学 与COPD表型相关的特征，特别是频繁加重表型; 2）确定 5年以上血清代谢组纵向变化与COPD进展的关系 随访; 3）研究通过肺减容手术减少过度充气对 血清代谢组本提案中规划的工作利用了 密歇根大学密歇根区域综合代谢组学资源核心。的 通过成功完成本建议书获得的初步数据和严格培训， 博士Labaki将在未来的R 01应用中领导靶向代谢组学验证研究和临床试验。

PROJECT SUMMARY / ABSTRACT Chronic obstructive pulmonary disease (COPD) is prevalent, costly and associated with high morbidity and mortality. It is also a remarkably heterogeneous condition with regards to both its pulmonary and systemic manifestations. The mechanistic underpinnings of this heterogeneity remain poorly understood and treatment approaches for patients with COPD are still mostly the same. Metabolomics is the large-scale study of low molecular weight compounds, commonly known as metabolites, within cells, tissues or biological fluids. Preliminary data suggest that specific metabolomics profiles are associated with poor clinical outcomes in COPD and may reveal unique insights into disease heterogeneity. Such investigations could ultimately lead to the development of new therapeutic approaches which are sorely needed. However, the potential of metabolomics remains largely untapped in COPD. This K23 mentored career development application proposes a coordinated 5-year training and research plan to allow Wassim Labaki, MD, MS to achieve his long-term goal of becoming an independent physician-scientist. His scientific focus will be on patient-oriented clinical and translational COPD research, specifically in the field of metabolomics. Dr. Labaki will be mentored and advised by experts not only in metabolomics, but also bioinformatics and clinical research to help him hone such skills during the award period. His training plan will include advanced coursework at the University of Michigan School of Public Health and Department of Computational Medicine and Bioinformatics, further supplemented by hands-on practical experience in the metabolomics laboratories at the University of Michigan and regular participation in various national and institutional workshops and conferences. This application will take advantage of the clinically well-characterized NIH-funded SPIROMICS COPD cohort to identify mechanistic metabolic pathways involved in COPD pathogenesis and progression that could be intervened upon early in the disease course. The specific Aims of this project are to: 1) define the serum metabolomics profiles associated with COPD phenotypes, especially the frequent exacerbator phenotype; 2) determine the relationship between longitudinal changes in the serum metabolome and progression of COPD over 5 years of follow-up; and 3) investigate the impact of reduction in hyperinflation via lung volume reduction surgery on the serum metabolome. The work planned in this proposal leverages the unique infrastructure and expertise of the Michigan Regional Comprehensive Metabolomics Resource Core at the University of Michigan. The preliminary data and rigorous training acquired through the successful completion of this proposal will position Dr. Labaki to lead targeted metabolomics validation studies and clinical trials in future R01 applications.