Integrative metabolomics of bronchopulmonary dysplasia in extremely low gestational age infants

极低胎龄儿支气管肺发育不良的综合代谢组学

• 批准号: 10211037
• 负责人: PHILIP L. BALLARD
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211037
• 关键词: Acute; Adrenal Cortex Hormones; African American; Age; Aspirate substance; Biochemical; Biochemical Pathway; Biological; Biological Markers; Bronchopulmonary Dysplasia; Cessation of life; Childhood; Cohort Studies; Development; Diagnosis; Disease; Early Diagnosis; Early treatment; Environment; Environmental Exposure; Ethnic Origin; Ethnic group; Extremely low gestational age newborn; Genetic; Genetic Processes; Genetic study; Genomics; Gestational Age; Goals; Growth; Health; Infant; Intervention; Knowledge; Liquid substance; Lung; Lung diseases; Measures; Medical; Molecular; Mothers; Outcome; Pathogenesis; Pathway interactions; Patient Self-Report; Pharmaceutical Preparations; Physiological Processes; Physiology; Population; Population Heterogeneity; Postnatal respiratory distress; Pregnancy; Premature Infant; Prevention; Process; Quantitative Trait Loci; Race; Resources; Risk; Role; Severities; Sum; Testing; Therapeutic; Time; Urine; Variant; biomarker development; clinical biomarkers; cohort; disorder risk; early detection biomarkers; ethnic difference; genome wide association study; genomic locus; high risk; high risk population; improved; infant outcome; inhaled nitric oxide; insight; knowledge base; lung development; metabolic profile; metabolome; metabolomics; multiple omics; novel; novel marker; nutrition; postnatal; premature; prevent; programs; racial and ethnic; racial diversity; respiratory; respiratory morbidity; response; social; supplemental oxygen; surfactant; targeted treatment; time use; urinary

PROJECT SUMMARY/ABSTRACT Bronchopulmonary dysplasia (BPD) in preterm infants is a common and often severe lung disease with long term sequelae. Rates of BPD vary between racial/ethnic groups, which may be due to differences in genetic ancestry or environment factors. Changes in the biochemical composition of biofluids (the metabolome) reflect the sum of both genetics and the environment, and thus characterizing these changes offers a broader view of the disease process as compared to genetic studies alone. Our goal is to increase our understanding of the biological basis of BPD and response to interventions in genetically diverse preterm infants at high risk of dis- ease. We hypothesize that there are temporal changes in the urinary and tracheal aspirate (TA) metabolome of the premature infant that are associated with respiratory outcomes and interventions, and that some of these changes vary by infant genetic ancestry. We will test our hypothesis with three specific aims. Specific Aim 1: Longitudinal characterization of the urinary and lung fluid metabolome of preterm infants. We will measure longitudinal changes in metabolic profiles of urine and tracheal aspirates in two cohorts of preterm infants at high risk of BPD from three racial/ethnic groups. We will identify changes in the metabolome of infants that are associated with respiratory status (diagnosis of BPD and later respiratory outcomes) and inter- ventions (e.g. type of nutrition, iNO therapy, corticosteroids, and other medications). Results from this aim will provide new information on the biofluid metabolome of preterm infants, biomarkers of disease and response to interventions, and insight into postnatal lung development and disease pathogenesis. Specific Aim 2: Examine the contribution of genetic ancestry, race and ethnicity on longitudinal changes in the biofluid metabolome of preterm infants. We will investigate the contribution of genetic ancestry and maternal self- reported race/ethnicity on temporal changes in the biofluid metabolome of premature infants. We will identify metabolites and pathways whose trajectories are associated with genomic ancestry independent of maternal race/ethnicity, and identify those under stronger genetic vs. social/ environmental determination. Results from this aim will provide new information as to the role of genetics on the biofluid metabolome of preterm infants as it relates to racial/ethnic differences in BPD and response to interventions. Specific Aim 3: Integrate genomic and metabolomic studies of BPD. We will identify novel metabolite quantitative trait loci (mQTL) in high risk preterm infants using a two-step approach that leverages variation in local genetic ancestry, and develop a resource to empower multi-omic studies of BPD. We will then combine this information with a genome-wide association study (GWAS) of BPD by integrating metabolomic and genomic associations in the same infants to identify novel genetic loci and biochemical pathways involved in the development and pathogenesis of BPD. Relevance: Results from this proposal will advance our understanding of disease pathogenesis in high risk preterm infants, and support the development of biomarkers and precision-targeted therapies.

项目摘要/摘要 早产儿中的支气管肺发育不良（BPD）是一种常见且经常严重的肺部疾病，长期很长 术语后遗症。种族/族裔之间的BPD率有所不同，这可能是由于遗传的差异 祖先或环境因素。生物流体（代谢组）的生化组成的变化反映 遗传学和环境的总和，从而表征这些变化的总和可以更广泛地看出 与仅基因研究相比，疾病过程。我们的目标是提高我们对 BPD的生物学基础以及对遗传多样化婴儿干预措施的反应 舒适。我们假设尿液和气管抽吸（TA）代谢组有时间变化 与呼吸结局和干预措施相关的早产婴儿，其中一些婴儿 婴儿遗传血统的变化有所不同。我们将以三个特定目标检验我们的假设。具体目标1： 早产儿的尿和肺液代谢组的纵向表征。我们将 测量在两个早产群中尿液和气管抽吸的代谢谱的纵向变化 来自三个种族/族裔的BPD风险高的婴儿。我们将确定代谢组的变化 与呼吸状态有关的婴儿（BPD诊断和后来的呼吸结局）和间 班级（例如，营养类型，INO治疗，皮质类固醇和其他药物）。这个目标的结果将 提供有关早产，疾病生物标志物的生物流体代谢组的新信息以及对 干预措施，并洞悉产后发育和疾病发病机理。具体目标2： 检查遗传血统，种族和种族对生物流体纵向变化的贡献 早产婴儿的代谢组。我们将研究遗传血统和母体自我的贡献 报告的种族/民族是关于早产儿生物流体代谢组的时间变化的种族/种族。我们将确定 代谢物和轨迹与基因组血统相关的途径与母体无关 种族/种族，并确定在更强的遗传与社会/环境决定下的种族/种族。结果 这个目标将提供有关遗传学对早产的生物流体代谢组作用的新信息 它涉及BPD的种族/种族差异和对干预措施的反应。特定目标3：整合基因组 BPD的代谢组学研究。我们将确定具有高风险的新型代谢产物定量特质基因座（MQTL） 早产儿使用两步方法，该方法利用局部遗传血统的变化，并发展 资源以赋予BPD的多词研究能力。然后，我们将这些信息与全基因组结合在一起 BPD的协会研究（GWAS）通过将同一婴儿的代谢组和基因组关联整合到 确定与BPD发育和发病机理有关的新型遗传基因座和生化途径。 相关性：该提案的结果将提高我们对高风险中疾病发病机理的理解 早产儿，并支持生物标志物和精确靶向疗法的发展。