Adult Biomarkers in Neonatal Brain Injury and Development

项目摘要 循环脑损伤生物标志物已在成人中进行了广泛的研究，但我们没有临床可用的 急性识别新生儿常见脑特异性损伤的生物标志物，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 治疗高危新生儿。在NICU中采用脑损伤生物标志物的障碍是缺乏 生长期婴儿的规范性数据，早产的影响，需要相对较大的样本量， 外部验证的研究。这项提案的总体目标是开发一种多标记循环脑 新生儿IVH和HIE的损伤生物标志物面板，使用充分研究的成人生物标志物，以提供 目前标准治疗和未来研究治疗的疗效，并提供早期 预测信息这项提议的核心假设是，循环脑中特定的蛋白质水平 在早产儿和HIE新生儿的0-7天内连续测量可提供早期损伤 检测，预测婴儿死亡或中重度神经功能障碍的风险，预测治疗效果 用于治疗性低温，并作为将新生儿分诊到适当的新研究的基础。 降低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、S100 B、NSE和GFAP）和4种脑损伤相关蛋白的复合组 (IL-1 IL-6、IL-8、VEGF）作为脑损伤的生物标志物在训练中在成人中被广泛研究（Johns霍普金斯 Medicine，巴尔的摩，JHM）和外部测试（All Children's Hospital JHM，St.彼得堡，FL）队列。 1）确定脑损伤生物标志物的循环水平是否依赖于 使用来自早产儿和足月儿的纵向血液样本的现有队列的胎龄 （N=400，妊娠23-40周）入住NICU，无临床脑损伤，以确定 胎龄在基线水平。2)在HIE中确定循环脑损伤生物标志物水平， 治疗性低温后预测不良结局，包括A）7-10天时的MRI异常和B） 24个月时死亡或神经系统残疾。3)在IVH中确定循环脑损伤生物标志物水平是否在 VLBW早产新生儿出生后的前7天A）诊断IVH，B）预测6岁时PVH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入组 在JHM（训练集）和ACH JHM（测试集）进行外部验证。通过研究血脑屏障 依赖和独立的生物标志物蛋白质在成人中进行了详尽的研究， 敏感的多重制药级格式，使用大型培训和测试队列，我们将确认可推广性 和治疗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.