Cord Blood Adductomics in Bronchopulmonary Dysplasia

支气管肺发育不良的脐带血加合物组学

• 批准号: 10580523
• 负责人: Karen K Mestan
• 金额: $ 7.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10580523
• 关键词: Cord; Blood; Adductomics; Bronchopulmonary; Dysplasia

PROJECT SUMMARY Bronchopulmonary dysplasia (BPD) remains the most common chronic lung disease of infancy, affecting 40% of infants born extremely preterm (EPT, born at <28 completed weeks gestation). Severe BPD is characterized by chronic supplemental oxygen exposure, mechanical ventilation dependence, and prolonged and recurrent hospitalizations within the first year of life. Despite advances in neonatal intensive care unit (NICU) management, the incidence of BPD remains unacceptably high. Our research seeks to identify novel, reliable and mechanistic-based biomarkers that can help guide management of our critically ill EPT patients, and inform the development of new approaches to BPD prevention. A well-supported scientific premise is that environmental exposures that induce lung injury through oxidative stress (OS) play a central role in BPD pathophysiology. Putative early life exposures include uteroplacental insufficiency during pregnancy, and hyperoxia in the early postnatal period. Reactive oxygen and nitrogen species are central to BPD pathophysiology as they directly damage DNA and proteins necessary for lung growth and repair. These electrophiles enter the blood from absorption in the lungs from oxidation of lipids and other molecules. Once in the blood, electrophiles react with available proteins to form addition products, or adducts. When bound to human serum albumin (HSA), these adducts become more stable (28 days in circulation) than the scavenged reactive electrophiles. The HSA-Cys34 residue is an important “nucleophilic hotspot” for OS-related adducts, accounting for 80% of plasma antioxidant capacity. Unbiased, untargeted adductomics pipelines for HSA-Cys34 have recently been developed, which have led to discovery of long-lived exposure biomarkers of chronic disease arising from OS. Application of untargeted adductomics in an EPT infant population would provide new opportunities to investigate the neonatal exposome as it relates to BPD. In the proposed study, we will utilize the resources of a large well-established NICU birth cohort coupled with the unique resources of the Northwestern Adductomics Lab. Our central hypothesis is that OS-related adducts can identify meaningful perinatal and neonatal exposures that predict BPD. In Aim 1, will identify HSA-Cys34 adducts and intrauterine exposure pathways of BPD through untargeted and targeted adductomics of archived cord blood plasma from 100 EPT births (N=50 BPD cases and 50 non-BPD controls), and 50 term control births. We will quantify abundant and discordant adducts, stratified by infant gender, gestational age, placental histologic lesions of uteroplacental insufficiency, and with other perinatal covariates. In Aim 2, we will perform targeted adductomics in postnatal blood to test the hypothesis that HSA-Cys34 adducts that correlate with postnatal cumulative oxygen exposure are predictive of BPD. We will prospectively enroll 50 EPT infants at two Level III+ NICUs of the Prentice Birth Cohort, and collect postnatal blood at 1 month, 2 months, and 36 weeks corrected age (primary endpoint for BPD diagnosis).

项目摘要 支气管肺发育不良（BPD）仍然是婴儿期最常见的慢性肺部疾病， 40%的婴儿极早产（EPT，妊娠<28周出生）。严重的BPD是 其特征在于慢性补充氧气暴露、机械通气依赖和长期 以及出生后第一年内的反复住院。尽管新生儿重症监护室（NICU）取得了进展， 尽管如此，BPD的发病率仍然高得不可接受。我们的研究旨在找出新颖可靠的 和基于机制的生物标志物，可以帮助指导我们的重症EPT患者的管理， 开发预防BPD的新方法。一个得到充分支持的科学前提是， 通过氧化应激（OS）诱导肺损伤的暴露在BPD病理生理学中起中心作用。 推定的生命早期暴露包括妊娠期子宫胎盘功能不全， 产后时期活性氧和氮是BPD病理生理学的核心，因为它们直接 损伤肺生长和修复所必需的DNA和蛋白质。这些亲电体进入血液， 通过脂质和其他分子的氧化在肺部吸收。一旦进入血液，亲电体就会与 可利用的蛋白质形成加成产物或加合物。当与人血清白蛋白（HSA）结合时，这些 加合物变得比清除的活性亲电体更稳定（循环28天）。HSA-Cys34 残基是OS相关加合物的重要“亲核热点”，占血浆抗氧化剂的80 容量最近已经开发了用于HSA-Cys 34的无偏倚、无靶向内收管切开术管道，其 导致发现由OS引起的慢性疾病的长寿命暴露生物标志物。 EPT婴儿人群的内收管切开术将为研究新生儿疾病提供新的机会。 因为它与BPD有关。在拟议的研究中，我们将利用大型完善的新生儿重症监护室的资源 队列加上西北内收手术实验室的独特资源。我们的核心假设是， OS相关加合物可以识别有意义的围产期和新生儿暴露，预测BPD。目标1： 通过非靶向和靶向鉴定HSA-Cys 34加合物和BPD宫内暴露途径 来自100例EPT分娩（N=50例BPD病例和50例非BPD对照）的存档脐带血血浆的内收管切开术， 和50例足月对照分娩。我们将量化丰富和不协调的加合物，按婴儿性别分层， 胎龄、子宫胎盘功能不全的胎盘组织学病变以及其他围产期协变量。 在目标2中，我们将在出生后血液中进行靶向内收切断术，以检验HSA-Cys 34加合物 与出生后累积氧暴露量相关的基因是BPD的预测因子。我们将招募50名 在普伦蒂斯出生队列的两个III级+NICU的EPT婴儿，并在1个月、2个月、 和36周校正年龄（BPD诊断的主要终点）。