Adult Biomarkers in Neonatal Brain Injury and Development

项目概要 循环脑损伤生物标志物已在成人中进行了广泛研究，但我们还没有临床可用的 生物标志物可敏锐识别新生儿常见的脑特异性损伤，例如脑室内出血 （IVH）和新生儿缺氧缺血性脑病（HIE），以跟踪治疗效果或评估新的治疗效果 对高危新生儿进行治疗。在 NICU 中采用脑损伤生物标志物的障碍是缺乏 成长中婴儿的规范数据、早产的影响、需要相对较大的样本量且不需要大量样本 具有外部验证的研究。该提案的总体目标是开发多标记循环大脑 使用经过充分研究的成人生物标志物，为新生儿 IVH 和 HIE 建立损伤生物标志物组，以提供以下基准： 当前标准治疗和未来研究治疗的疗效，并提供早期治疗 预后信息。该提案的中心假设是循环大脑特定蛋白质水平 对早产儿和患有 HIE 的新生儿在出生后第 0-7 天进行连续测量将提供早期损伤 检测，预测有死亡或中重度神经功能障碍风险的婴儿，预测治疗效果 用于治疗性低温，并作为对新生儿进行分类以适应新研究的基础 降低发病率并改善结果的疗法。为了检验我们的假设，我们将利用一部小说 4 种脑特异性蛋白（BDNF、S100B、NSE 和 GFAP）和 4 种脑损伤相关蛋白的多重组合 （IL-1、IL-6、IL-8、VEGF）在成人中作为脑损伤的生物标志物在训练中进行了广泛研究（约翰·霍普金斯大学 医学，巴尔的摩，JHM）和外部测试（所有儿童医院 JHM，圣彼得堡，佛罗里达州）队列 具体目标如下： 1) 确定脑损伤生物标志物的循环水平是否取决于 使用来自早产儿和足月婴儿的现有纵向血液样本队列确定孕龄 （N=400，妊娠 23-40 周）入住 NICU，无临床脑损伤，以确定效果 胎龄处于基线水平。 2) 在 HIE 中确定循环脑损伤生物标志物水平是否在 低温治疗后可预测不良后果，包括 A) 7-10 天的 MRI 异常和 B) 24 个月时死亡或神经功能障碍。 3) 确定 IVH 期间循环脑损伤生物标志物水平 VLBW 早产儿出生后的前 7 天 A) 诊断 IVH，B) 预测 6 岁时 PVWMI 脑损伤 周和 C) 24 个月时神经功能障碍。这两个目标都将同时进行 IVH 和 HIE 注册 在 JHM（训练集）和 ACH JHM（测试集）中进行外部验证。通过关注血脑屏障面板 以创新和高度的方式对成人的依赖和独立生物标志物蛋白进行了详尽的研究 敏感的多重制药级格式，使用大型培训和测试队列，我们将确认普遍性 及其对新生儿脑损伤的疗效。

Project Summary Circulating brain injury biomarkers have been studied extensively in adults, yet we have no clinically available biomarkers to acutely identify brain specific injury common in neonates, such as intraventricular hemorrhage (IVH) and neonatal hypoxic-ischemic encephalopathy (HIE), to follow therapeutic efficacy or evaluate new therapies in neonates at risk. Hurdles to adoption of brain injury biomarkers in the NICU have been the lack of normative data in the growing infant, effect of prematurity, relatively large sample volumes needed and no large studies with external validation. The overall goal of this proposal is to develop a multimarker circulating brain injury biomarker panel for neonatal IVH and HIE using well studied adult biomarkers, to provide a benchmark of therapeutic efficacy for current standard treatments and future investigational treatments, and to provide early prognostic information. The central hypothesis of this proposal is that circulating brain specific protein levels measured serially over days 0-7 of life in premature neonates and neonates with HIE will provide early injury detection, predict infants at risk for death or moderate-severe neurologic disability, predict therapeutic efficacy for therapeutic hypothermia, and serve as a basis for triaging neonates to appropriate new investigational therapies to decrease morbidity and improve outcomes. To examine our hypothesis we will utilize a novel multiplex panel of 4 brain specific proteins (BDNF, S100B, NSE and GFAP) and 4 brain injury related proteins (IL-1, IL-6, IL-8, VEGF) studied extensively in adults as biomarkers of brain injury, in training (Johns Hopkins Medicine, Baltimore, JHM) and external test (All Children’s Hospital JHM, St. Petersburg, FL) cohorts in the following Specific Aims: 1) Determine if circulating levels of brain injury biomarkers are dependent on gestational age using an existing cohort of longitudinal blood samples from premature and full term infants (N=400, 23-40 weeks gestation) admitted to the NICU without clinical brain injury to determine the effect of gestational age on baseline levels. 2) Determine in HIE if circulating brain injury biomarker levels during and after therapeutic hypothermia predict adverse outcomes including A) MRI abnormalities at 7-10 days and B) death or neurologic disability at 24 months. 3) Determine in IVH if circulating brain injury biomarker levels during the first 7 days of life in VLBW premature neonates are A) diagnostic for IVH, B) predict PVWMI brain injury at 6 weeks and C) neurologic disability at 24 months. Both of these aims will use concurrent IVH and HIE enrollment at JHM (training set) and ACH JHM (test set) for external validation. By focusing on a panel of blood brain barrier dependent and independent biomarker proteins studied exhaustively in adults, in a innovative and highly sensitive multiplex Pharma grade format, using large training and test cohorts we will confirm generalizability and efficacy in neonatal brain injury.