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

项目摘要/摘要 全球每年有250万名婴儿在怀孕不到32周时出生，其中约7.5万人 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，称为 支气管肺发育不良(BPD)，表现为肺功能低下，需要长期机械治疗 通风和氧疗，并容易导致较差的神经发育结果。此外，这些 儿童表现出对肺部感染的脆弱性增加，通常需要在#年的第一年重新住院。 生活。摘要严重的支气管肺发育不良是儿童肺部疾病中最重要的疾病之一。 美国，随着越来越多的极早产儿存活下来离开美国，发病率不断上升 重症监护室。 治疗bpd的一种常用药物是全身类固醇，包括皮质类固醇地塞米松。 和氢化可的松，它产生可变和不可预测的短期肺部益处，但 与神经发育障碍和其他重要的副作用有关，如生长发育迟缓， 高血压和骨矿化减少。考虑到不同的临床疗效和不良反应的高风险 重要的是，确定一组患有BPD的婴儿谁将从类固醇治疗中受益最大， 使不良事件的风险更容易被接受。已知有一些功能上重要的遗传变异 在相似的患者群体中影响类固醇代谢和反应，所以我们知道类固醇的变异性 这种反应可能在一定程度上有基因基础。 在一个前瞻性招募的多点队列中(N=150)，我们将评估哪些基因组和代谢标记 与BPD的激素反应相关。我们还将利用之前发布的知识和试点数据 采取不可知的方法，确定早产儿激素反应的基因组生物标记物 全身应用地塞米松或氢化可的松治疗BPD。我们还会比较尿液和血浆 激素应答者和无应答者之间的药物代谢谱寻找治疗前或早期 药物疗效的治疗标志物。该研究计划的总体目标是阐明基因组和 代谢组学生物标志物的临床反应，作为识别一组婴儿最多的机制 良好的风险收益比，将BPD治疗领域推向精准医学。这个项目很适合 NICHD产科和儿科药理学分会的使命，因为它涉及一个 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。这个 现代药理学研究工具的系统应用将使某些早产的识别成为可能 先天或疗程早期的婴儿，他们将具有临床益处&>；毒性风险，允许 这组婴儿的个人化治疗。

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.