Integrative Metabolomics of Asthma Severity

哮喘严重程度的综合代谢组学

• 批准号: 8752947
• 负责人: JESSICA A LASKY-SU
• 金额: $ 71.67万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8752947
• 关键词: Amino Acids; Arachidonic Acids; Asthma; Bayesian Analysis; Biological; Biological Markers; Characteristics; Childhood Asthma; Clinical; Clinical Trials; Costa Rican; Data; Disease; Disease Marker; Enrollment; Gene Expression; Genetic; Genomics; Health; Hypermethylation; Hypoxia; Individual; Left; Link; Lipids; Measures; Metabolic; Molecular; Nucleotides; Phenotype; Prevention approach; Primary Prevention; Process; Public Health; Quantitative Trait Loci; Recording of previous events; Research; Resources; Schools; Severities; Severity of illness; Therapeutic; Tryptophan; Tryptophan Metabolism Pathway; Variant; Whole Blood; Work; asthmatic patient; cohort; computer based statistical methods; genome wide association study; genome-wide; meetings; metabolomics; novel; organic acid; proband; programs; public health relevance; response; sugar

DESCRIPTION (provided by applicant): Asthma exacerbations are the most common health-related cause of lost school and work days and contribute substantially to the more than $50 billion dollars spent on asthma annually.1 Therefore any systematic reduction in asthma exacerbations will have a large public health impact. Asthma is a heritable disease2,3 and although a number of molecular determinants have been identified4, much remains to be understood about how these variants impact the severity of disease. Metabolic profiling, the systematic analysis of all metabolites, has been used successfully to identify new biomarkers for several diseases. Metabolites have the distinct advantage of being more proximal markers of disease processes than are transcriptional, translational or post-translational changes. Metabolic profiling is also able to capture the history of relevant past exposures such as hypermethylation and response to hypoxia, both of which are highly relevant for asthma. To date, metabolomics studies have been limited in size and scope for asthma.5,6 The metabolome remains an untapped resource and has the potential to comprehensively characterize many aspects of asthma, including the severity of disease.7,8 The over arching hypothesis of this proposal is that key metabolites will elucidate our understanding of asthma severity through the use of metabolomic profiling and the integration with other forms of molecular data. We will 1) identify individual metabolites and metabolic profiles associated with asthma severity in both untargeted and candidate approaches; 2) Integrate metabolomics data with genome-wide genetic (i.e. SNP) and genomic (i.e. gene expression) data 3) identify metabolomic signatures that accurately predict asthma exacerbations and differentiate asthma severity through the integration of environmental, clinical, genetic, genomic, and metabolomics data. This will represent the largest metabolomics study in asthmatic patients to date and enable the identification of important distinctions between individuals with varying asthma severity, potentially motivating specific therapeutic and primary prevention approaches for exacerbations.

描述（由申请人提供）：哮喘急性发作是造成学生和工作日损失的最常见的健康相关原因，每年用于哮喘的费用超过500亿美元。1因此，任何系统性减少哮喘急性发作的措施都将对公共卫生产生重大影响。哮喘是一种遗传性疾病2，3，尽管已经确定了许多分子决定因素4，但关于这些变异如何影响疾病的严重程度仍有许多问题有待了解。代谢谱，所有代谢物的系统分析，已成功地用于确定几种疾病的新的生物标志物。代谢产物具有作为比转录、翻译或翻译后变化更接近疾病过程的标志物的明显优势。代谢谱还能够捕获相关的过去暴露的历史，例如高甲基化和对缺氧的反应，这两者都与哮喘高度相关。迄今为止，代谢组学研究在哮喘的规模和范围方面受到限制。5，6代谢组学仍然是一种未开发的资源，有可能全面表征哮喘的许多方面，包括疾病的严重程度。7，8.这项建议的过度假设是，通过使用代谢组学分析和与其他形式的代谢物的整合，关键代谢物将阐明我们对哮喘严重程度的理解。分子数据我们将1）在非靶向和候选方法中识别与哮喘严重程度相关的个体代谢物和代谢谱; 2）将代谢组学数据与全基因组遗传学数据相结合（即SNP）和基因组（即基因表达）数据3）通过整合环境、临床、遗传、基因组，和代谢组学数据。这将代表迄今为止在哮喘患者中进行的最大规模的代谢组学研究，并能够识别不同哮喘严重程度个体之间的重要区别，可能激发针对急性发作的特定治疗和一级预防方法。