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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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，术语后遗症。 BPD 的发病率因种族/族裔群体而异，这可能是由于遗传差异所致血统或环境因素。生物体液生化成分（代谢组）的变化反映了遗传和环境的总和，从而描述这些变化提供了更广阔的视野与单独的基因研究相比，疾病的过程。我们的目标是增加我们对 BPD 的生物学基础以及对遗传多样性早产儿干预的反应舒适。我们假设尿液和气管抽吸物（TA）代谢组存在时间变化与呼吸系统结果和干预措施相关的早产儿，其中一些变化因婴儿遗传血统而异。我们将通过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抽吸物代谢特征的纵向变化来自三个种族/族裔群体的 BPD 高风险婴儿。我们将确定代谢组的变化与呼吸状态（BPD 的诊断和后来的呼吸结果）相关的婴儿以及预防措施（例如营养类型、iNO 疗法、皮质类固醇和其他药物）。这一目标的结果将提供有关早产儿生物体液代谢组、疾病生物标志物和反应的新信息干预措施，并深入了解产后肺部发育和疾病发病机制。具体目标2：检查遗传血统、种族和民族对生物体液纵向变化的贡献早产儿的代谢组。我们将研究遗传血统和母亲自我的贡献报告了种族/民族对早产儿生物体液代谢组时间变化的影响。我们将确定其轨迹与基因组祖先相关的代谢物和途径，独立于母体种族/民族，并识别那些受更强的遗传与社会/环境决定的人。结果来自这一目标将提供关于遗传学对早产儿生物体液代谢组的作用的新信息它与 BPD 的种族/民族差异和对干预措施的反应有关。具体目标 3：整合基因组和 BPD 的代谢组学研究。我们将在高风险中识别新的代谢物数量性状位点（mQTL）早产儿采用两步法，利用当地遗传祖先的变异，并开发一种促进 BPD 多组学研究的资源。然后我们会将这些信息与全基因组范围的信息结合起来通过整合同一婴儿的代谢组学和基因组关联来进行 BPD 关联研究 (GWAS) 确定参与 BPD 发展和发病机制的新遗传位点和生化途径。相关性：该提案的结果将增进我们对高风险疾病发病机制的理解早产儿，并支持生物标志物和精准靶向治疗的开发。