Adult Biomarkers in Neonatal Brain Injury and Development

项目摘要 循环脑损伤生物标志物已经在成人中得到了广泛的研究，但我们还没有临床可用的。 生物标记物可准确识别新生儿常见的脑损伤，如脑室出血 (IVH)和新生儿缺氧缺血性脑病(HIE)，追踪治疗效果或评估新的 高危新生儿的治疗。在NICU采用脑损伤生物标记物的障碍是缺乏 生长中婴儿的标准化数据，早产的影响，需要相对较大的样本量，不需要很大的样本量 具有外部验证的研究。这项提议的总体目标是开发一个多标记循环大脑 新生儿IVH和HIE的损伤生物标记物小组使用经过充分研究的成人生物标记物，为 当前标准治疗和未来研究治疗的疗效，并提供早期 预后信息。这一提议的中心假设是循环中的大脑特定蛋白质水平 早产儿和缺氧缺血性脑病新生儿出生后0-7天连续测量将提供早期损伤 检测，预测有死亡风险的婴儿或中-重度神经残疾，预测治疗效果 用于治疗性低温，并作为新生儿分流的基础，以适当的新的研究 减少发病率和改善结果的治疗。为了检验我们的假设，我们将利用一本小说 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、血管内皮生长因子)作为训练中脑损伤的生物标志物，在成人中被广泛研究(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，圣彼得堡，佛罗里达州)队列 以下具体目标：1)确定脑损伤生物标志物的循环水平是否依赖于 利用现有的早产儿和足月儿纵向血样队列研究胎龄 (n=400，妊娠23-40周)入院无临床脑损伤的NICU，以确定疗效 胎龄在基线水平。2)在HIE中确定循环脑损伤生物标记物水平 治疗后体温过低可预测不良结果，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)在IVH中确定循环脑损伤生物标志物水平 VLBW早产儿出生前7天A)诊断为IVH，B)在6岁时预测PVWMI脑损伤 C)24个月时的神经功能障碍。这两个目标都将同时使用IVH和HIE注册 在JHM(训练集)和ACH JHM(测试集)进行外部验证。通过专注于一组血脑屏障 依赖和独立的生物标记物蛋白在成人中进行了详尽的研究，具有创新性和高度的 敏感的多元化医药等级格式，使用大型培训和测试队列，我们将确认普适性 以及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.