Less Lumping, Smarter Splitting: Genomics and Metabolomics of Systemic Steroid Response in Bronchopulmonary Dysplasia

项目总结/摘要 2.5全世界每年有100万婴儿在妊娠不到32周时出生，其中约有75，000名 他们出生在美国。这些早产儿中的许多人会患上一种严重的肺部疾病， 支气管肺发育不良（BPD），表现为肺功能差，需要长时间机械通气 通气和氧气治疗，并倾向于较差的神经发育结果。另外这些 儿童对肺部感染表现出更大的脆弱性， 生活严重支气管肺发育不良是最重要的小儿肺部疾病之一， 在美国，发病率随着极早产儿存活到出院的人数的增加而增加。 重症监护室 BPD的一种常用药物治疗是全身性类固醇，包括皮质类固醇地塞米松 和氢化可的松，其产生可变的和不可预测的短期肺益处，但 与神经发育障碍和其他重要的副作用如生长发育迟缓有关， 高血压和骨矿化减少。考虑到临床疗效的可变性和不良反应的高风险， 因此，重要的是要确定一组BPD婴儿，他们将从类固醇治疗中获益最多， 使不良事件的风险更可接受。已知有一些功能重要的遗传变异， 影响类固醇代谢和类似患者人群反应，因此我们知道类固醇的变异性 这种反应可能部分是遗传基础。 在一个前瞻性招募的多中心队列（N=150）中，我们将评估基因组学和代谢组学标志物， 与BPD中的类固醇反应相关。我们还将利用先前公布的知识和试点数据， 采取不可知论的方法，以确定早产儿类固醇反应的基因组生物标志物， 用全身性地塞米松或氢化可的松治疗BPD。我们还会比较尿液和血浆 类固醇反应者和非反应者之间的药物代谢组学，以寻找治疗前或早期 药物疗效的治疗标志物。研究计划的总体目标是阐明基因组和 临床反应的代谢组学生物标志物，作为一种机制，以确定一组婴儿与最 有利的风险受益比，将BPD治疗领域推向精准医学。这个项目适合 以及与NICHD产科和儿科药理学分支的使命，因为它解决了一个 具有高度可变和不可预测的药物反应（疗效和毒性）的严重儿科疾病。的 现代药理学研究工具的系统应用将允许识别某些早产儿， 婴儿，无论是先验的或早期的治疗过程中，谁将有临床效益>>毒性风险，允许 个性化的治疗方法。

Project Summary/Abstract 2.5 million infants are born at less than 32 weeks gestation worldwide every year, with approximately 75,000 of them born in the US. Many of these preterm infants develop a severe form of lung disease called Bronchopulmonary Dysplasia (BPD), which manifests as poor lung function requiring prolonged mechanical ventilation and oxygen therapy, and predisposing to poorer neurodevelopmental outcomes. In addition, these children exhibit increased fragility to lung infections and often require hospital readmissions in the first year of life. Severe Bronchopulmonary Dysplasia is one of the most important pediatric pulmonary disorder in the United States, increasing in incidence as increasing numbers of extremely preterm infants survive to leave the ICU. One commonly used drug therapy for BPD is systemic steroids, including the corticosteroids dexamethasone and hydrocortisone, which produces variable and unpredictable short term pulmonary benefit, but are associated with neurodevelopmental impairment and other important side effects such as growth stunting, hypertension and decreased bone mineralization. Given the variable clinical efficacy and high risk for adverse effects, it is important to identify a group of infants with BPD who will benefit the most from steroid therapy, making the risk of adverse events more acceptable. There are functionally important genetic variants known to impact steroid metabolism and response in similar patient populations, so we know that variability in steroid response likely has, in part, genetic underpinnings. In a prospectively recruited multi-site cohort (N=150), we will assess genomic and metabolomic markers which correlate with steroid response in BPD. We will capitalize on prior published knowledge and pilot data, as well as take an agnostic approach, to identify genomic biomarkers of steroid response among preterm infants treated with systemic dexamethasone or hydrocortisone for BPD. We will also compare the urine and plasma pharmacometabolome between steroid responders and non-responders to look for pre-treatment or early treatment markers of drug efficacy. The overall goal of the research program is to elucidate genomic and metabolomics biomarkers of clinical response, as a mechanism to identify a group of infants with the most favorable risk to benefit ratio, moving the field of BPD treatment towards precision medicine. This project fits well with the mission of the NICHD Obstetric and Pediatric Pharmacology branch, because it addresses a severe pediatric disease with highly variable and unpredictable drug response (efficacy and toxicity). The systematic application of modern pharmacology research tools will allow the identification of certain preterm infants, either a priori or early in the treatment course, who will have clinical benefit >>toxicity risk, allowing for personalized therapeutics in this group of infants.