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: 10396118
• 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/10396118
• 关键词: Acute; Adrenal Cortex Hormones; African American; Age; Aspirate substance; Biochemical; Biochemical Pathway; Biological; Biological Markers; Black American; 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; long-term sequelae; 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.

项目总结/摘要 早产儿支气管肺发育不良（BPD）是一种常见且往往严重的肺部疾病， 长期后遗症。BPD的发生率在种族/民族群体之间存在差异，这可能是由于遗传差异造成的。 祖先或环境因素。生物体液的生化组成（代谢组）的变化反映了 遗传学和环境的总和，从而表征这些变化提供了一个更广泛的观点， 与单独的遗传学研究相比，我们的目标是增加我们对 BPD的生物学基础和对遗传多样性早产儿高风险疾病干预的反应 放松。我们假设尿液和气管抽吸物（TA）代谢组存在时间变化 早产儿与呼吸结果和干预措施有关，其中一些 变化因婴儿遗传祖先而异。我们将用三个具体目标来检验我们的假设。具体目标1： 早产儿尿液和肺液代谢组的纵向特征。我们将 测量两组早产儿尿液和气管吸出物代谢谱的纵向变化 来自三个种族/民族的BPD高风险婴儿。我们将确定代谢组的变化， 与呼吸状态（BPD的诊断和随后的呼吸结果）相关的婴儿， 静脉（例如，营养类型，iNO治疗，皮质类固醇和其他药物）。这一目标的结果将 为早产儿的生物流体代谢组、疾病的生物标志物和对 干预，并深入了解出生后肺发育和疾病发病机制。具体目标二： 检查遗传祖先、种族和民族对生物流体纵向变化的贡献 早产儿的代谢组学。我们将调查遗传祖先和母亲自我的贡献， 报告了人种/种族对早产儿生物液体代谢组时间变化的影响。我们将确定 代谢物和途径，其轨迹与基因组祖先无关， 种族/民族，并确定那些在更强的遗传与社会/环境的决定。结果 这一目标将为遗传学对早产儿生物流体代谢组学的作用提供新的信息， 它涉及BPD的种族/民族差异和对干预措施的反应。具体目标3：整合基因组 和代谢组学研究。我们将在高风险人群中发现新的代谢物数量性状基因座（mQTL）， 早产儿使用两步方法，利用当地遗传祖先的变化， 资源，使多组学研究的BPD。然后我们将联合收割机将这些信息与全基因组的 通过整合同一婴儿的代谢组学和基因组学关联， 确定参与BPD发展和发病机制的新的遗传位点和生化途径。 相关性：这项建议的结果将促进我们对高危人群疾病发病机制的理解。 早产儿，并支持生物标志物和精确靶向治疗的发展。