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: 10571837
• 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/10571837
• 关键词: Acute; Adrenal Cortex Hormones; African American; Age; Biochemical; Biochemical Pathway; Biological; Biological Markers; Black American; Bronchopulmonary Dysplasia; Cessation of life; Childhood; Cohort Studies; Development; Diagnosis; Disease; Early Diagnosis; Early identification; Early treatment; Environment; Environmental Exposure; Ethnic Origin; Ethnic Population; 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 Assessment; Role; Severities; Sum; Testing; Therapeutic; Time; Trachea; Urine; Variant; aspirate; biomarker development; clinical biomarkers; cohort; disorder risk; early detection biomarkers; empowerment; 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 difference; racial diversity; racial population; 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/文摘