Adult Biomarkers in Neonatal Brain Injury and Development

新生儿脑损伤和发育中的成人生物标志物

• 批准号: 9549109
• 负责人: ALLEN D EVERETT
• 金额: $ 64.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9549109
• 关键词: Acute; Adoption; Adult; Atlases; Baltimore; Benchmarking; Biological Assay; Biological Markers; Birth; Blood; Blood - brain barrier anatomy; Blood specimen; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Cessation of life; Child; Childhood; Clinical; Data; Detection; Development; Diagnostic; Effectiveness; Enrollment; Enzyme-Linked Immunosorbent Assay; Evaluation; Future; Gestational Age; Glial Fibrillary Acidic Protein; Goals; Hypoxic Brain Damage; IL8 gene; Image; Immunoassay; Infant; Injury; Interleukin-1; Interleukin-6; Intervention Trial; Investigation; Investigational Therapies; Life; Literature; Longitudinal cohort; Low Birth Weight Infant; Magnetic Resonance Imaging; Measures; Medicine; Morbidity - disease rate; Neonatal; Neonatal Brain Injury; Neurodevelopmental Deficit; Neurodevelopmental Disability; Neurologic; Outcome; Pathway interactions; Pediatric Hospitals; Pregnancy; Premature Infant; Proteins; Research Design; Risk; Sampling; Severities; Testing; Therapeutic; Therapeutic Trials; Training; Treatment Efficacy; Triage; Validation; Vascular Endothelial Growth Factors; Very Low Birth Weight Infant; Vulnerable Populations; adverse outcome; age related; base; biomarker panel; brain cell; cell injury; cell type; cohort; cost; disability; early detection biomarkers; exhaustion; experience; improved; improved outcome; inflammatory marker; injured; innovation; intraventricular hemorrhage; natural hypothermia; neonatal hypoxic-ischemic brain injury; neonate; novel; novel diagnostics; novel therapeutics; premature; premature neonates; prognostic; protein biomarkers; response; standard care

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.

项目摘要 循环的脑损伤生物标志物已在成人中进行了广泛的研究，但我们没有临床上可用的 生物标志物可以急性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）遵循治疗效率或评估 在有风险的新生儿的疗法。 NICU中采用脑损伤生物标志物的障碍缺乏 不断增长的婴儿的正常数据，早产的效果，相对大样本体积和不大的效果 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 使用良好的成人生物标志物，用于新生儿IVH和HIE的伤害生物标志物面板，以提供基准 当前标准治疗和未来研究治疗的治疗效率，并提早提供 预后信息。该提议的中心假设是循环大脑特异性蛋白水平 在过早的新生儿和新生儿的生命的0-7天内串行测量将提供早期伤害 检测，预测有可能死亡或中度严重神经系统疾病的婴儿预测治疗效率 用于治疗性体温过低，并作为对新生儿进行分类新研究的基础 降低发病率并改善预后的疗法。为了审查我们的假设，我们将利用小说 4个脑特异性蛋白（BDNF，S100B，NSE和GFAP）和4个与脑损伤相关的蛋白质的多重面板 （IL-1，IL-6，IL-8，VEGF）在成年人中作为脑损伤的生物标志物进行了广泛的研究（Johns Hopkins 医学，巴尔的摩，JHM）和外部测试（佛罗里达州圣彼得堡的所有儿童医院JHM） 以下特定目的：1）确定脑损伤生物标志物的循环水平是否取决于 使用现有的纵向血液样本和完整婴儿的纵向血液样本使用的胎龄 （n = 400，23-40周妊娠）在没有临床脑损伤的情况下接受NICU，以确定 基线水平的妊娠年龄。 2）确定在HIE中是否在和 治疗性低温预测不良后果后，包括a）7-10天和b的MRI异常 24个月的死亡或神经疾病。 3）确定IVH是否在循环脑损伤生物标志物水平 VLBW早期新生儿的生命的前7天是a）IVH的诊断，b）预测PVWMI脑损伤在6 几周和c）24个月的神经功能障碍。这两个目标都将使用并发IVH和HIE入学 在JHM（训练集）和ACH JHM（测试集）进行外部验证。通过专注于血脑屏障面板 在成人中详尽研究的依赖和独立的生物标志物蛋白在创新且高度 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 并缓解新生儿脑损伤。