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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要循环的烤器生物标志物在Anults中进行了广泛的研究，但我们没有临床上的可用生物标志物可以急性识别新生儿常见的脑特异性损伤，例如静脉内出血 (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 具有外部验证的研究。新生儿IVH和Hie Hie良好研究的成人生物标志物的伤害生物标志物面板，以提供基准 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 在过早的新生儿和新生儿的生命中，序列序列测量，并带有早期伤害检测，预测婴儿有可能死亡或中等重度的拒绝性的婴儿，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发明的基础降低发病率并改善结果的疗法。 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双歧杆菌进行了广泛的研究（Johns Hopkins 医学，巴尔的摩，JHM）和外部测试以下特定目的：1）确定循环水平是否取决于使用纵向血液的妊娠年龄使用前后婴儿的纵向血液（n = 400，23-40周的妊娠）临床脑损伤接受了NICU，以确定基线水平上的胎龄。治疗性下降病预测不良后果后，包括a）7-10天和b的MRI异常 24个月时的死亡或神经疾病。 VLBW早期新生儿的生命前7天是a）IVH诊断周和c）24个月的神经系统疾病。在JHM（训练集）和ACH JHM（测试集）进行外部验证。依赖性和不动的生物标志物蛋白质详尽地研究了。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新生儿脑损伤的功效。