GFAP Biomarker of Whole Body Cooling Outcome and Efficacy in the Neonate with HIE

描述(申请人提供)：新生儿缺氧缺血性脑病(HIE)发生在2.5/1000足月活产中，中度HIE的死亡率为48-57%，重度HIE的死亡率为85-91%。患有中到重度HIE的新生儿在出生后6小时内接受轻度降温，死亡率和致残率下降12%-21%。尽管治疗新生儿缺氧缺血性脑病(HIE)的疗法正在开发中，但我们还没有临床可用的生物标志物来准确地识别脑特定损伤，跟踪HIE治疗效果或评估高危儿童的新疗法。目前的提案扩展了正在进行的父母试验，即NICHD新生儿研究网络(NRN)随机对照试验NCT00614744/NICHD-NRN-0036，“优化缺氧缺血性脑病的降温”。NRN试验将测试更长的降温时间(120比72小时)和/或更深的降温(320摄氏度比33.50摄氏度)是否会进一步减少18-22个月的死亡率和神经残疾，并将于2010年底开始招募患者(n=726)。目前的提议是一个独特的、时间敏感的机会，通过增加连续血液样本数据收集来扩大父母试验，从而能够识别和评估高危婴儿脑损伤的脑特异性循环生物标记物。这一建议的中心假设是，循环星形胶质细胞特异性蛋白水平作为脑白质损伤的生物标志物，在新生儿出生后0-6天连续测量，将预测有死亡风险或中-重度神经功能障碍的婴儿，将预测全身降温的治疗效果，并在未来的研究中作为对新生儿进行分类的基础，以降低发病率和改善预后。利用无偏倚血浆蛋白质组亚急性脑损伤生物标志物发现项目的初步数据，我们已经确认星形胶质细胞特异性蛋白胶质纤维酸性蛋白(GFAP)是新生儿HIE和ECMO支持下新生儿脑损伤的循环生物标志物，并与HIE缺氧性脑损伤的MRI指标显著相关。为了验证我们的假设，我们将利用一种新颖、快速(4小时)的GFAP测试来(1)确定循环GFAP的周降温水平是否可以预测不良结局，包括A)18-22个月的死亡或神经功能障碍，以及B)在NRN试验全身降温治疗组内和两组之间7-14天的MRI异常；2)确定循环GFAP的周冷期水平是否可以作为更长降温(120比72小时)和更深降温(32.00摄氏度对33.50摄氏度)治疗效果的基准。其意义在于，对新生儿脑损伤进行围产期快速检测，对于准确、准确地识别脑损伤、追踪HIE治疗的疗效或对高危新生儿进行新的治疗具有直接的临床意义。创新之处在于，通过专注于一种精致的大脑特异性蛋白质GFAP，我们将敏感性和疾病特异性问题降至最低，这些问题削弱了相对非特异性生物标志物的效用，如炎症介质和代谢副产物。 公共卫生相关性：我们将利用正在进行的NIH多中心随机临床试验中的成像和临床数据，测试更长时间和更深的全身降温，以更好地保护出生相关脑损伤婴儿的大脑。利用这些数据和我们将收集的血液样本，我们的儿科心脏病专家、新生儿专家、血液学家和流行病学家团队将确定循环中的脑蛋白--胶质纤维酸性蛋白(GFAP)是否可以作为脑损伤的快速衡量标准，以及降温疗法对大脑的保护效果如何。这一新方法的开发将：1)填补眼前的临床空白；2)利用已在NIH临床试验中进行的大量投资；3)使用简单的血液测试为家庭提供早期结果信息；4)指导临床医生对这些患病婴儿进行最佳治疗以保护大脑。

DESCRIPTION (provided by applicant): Neonatal hypoxic-ischemic encephalopathy (HIE) occurs in 2.5/1000 term live births with a death or neurologic disability rate of 48-57% with moderate HIE and 85-91% for severe HIE. Neonates with moderate to severe HIE who receive mild cooling within 6 hours of birth have a 12%-21% decline in death and disability. Although therapies are being developed to treat the neonate with HIE, we have no clinically available biomarkers to acutely identify brain-specific injury, to follow HIE therapy efficacy or to evaluate new therapies in the child at risk. The current proposal extends an ongoing parent trial, a randomized controlled NICHD Neonatal Research Network (NRN) Trial NCT00614744/NICHD-NRN-0036, "Optimizing Cooling for Hypoxic-Ischemic Encephalopathy". The NRN trial will test whether longer (120 vs 72 hours) and/or deeper (320C vs 33.50C) cooling further decreases death and neurologic disability at 18-22 months and will begin to enroll patients in late 2010 (n=726). The current proposal represents a unique, time-sensitive opportunity to extend the parent trial by adding serial blood sample data collection and thus enable the identification and evaluation of brain- specific circulating biomarkers of brain injury among infants at high risk. The central hypothesis of this proposal is that circulating astrocyte-specific protein levels, as a biomarker of white matter injury, measured serially over 0-6 days of life in neonates with HIE will predict infants at risk for death or moderate-severe neurologic disability, will predict therapeutic efficacy for whole body cooling, and in future studies serve as a basis for triaging neonates to appropriate therapies to decrease morbidity and improve outcomes. Using preliminary data based on a non-biased plasma proteomic discovery project of subacute brain injury biomarkers, we have identified that the astrocyte-specific protein glial fibrillary acidic protein (GFAP) is a circulating biomarker of brain injury in neonates with HIE and neonates on ECMO support and significantly associated with MRI measures of hypoxic brain injury with HIE. To examine our hypothesis we will utilize a novel, rapid (4 hour) test of GFAP to (1 determine whether peri-cooling levels of circulating GFAP predict adverse outcomes including A) death or neurologic disability at 18-22 months and B) MRI abnormalities at 7-14 days within and between the NRN trial whole body cooling treatment groups and 2) determine if peri-cooling levels of circulating GFAP can serve as a benchmark of longer cooling (120 vs 72 hours) and deeper cooling (32.00C vs 33.50C) therapeutic efficacy. The significance is that a rapid perinatal test of neonatal brain injury would be of immediate clinical benefit to acutely and accurately identify brain injury, to follow the efficacy of HIE therapy or to benchmark new therapies in neonates at risk. The innovation is that by focusing on an exquisitely brain-specific protein, GFAP, we minimize problems of sensitivity and disease specificity that diminish the utility of relatively non-specific biomarkers, such as inflammatory mediators and metabolic by- products. PUBLIC HEALTH RELEVANCE: We will take advantage of imaging and clinical data in an ongoing NIH multi-center randomized clinical trial to test longer and deeper whole body cooling to better protect the brain in babies with birth related brain injury. Using this data and blood samples that we will collect, our team of pediatric cardiologists, neonatologists, hematologists and epidemiologists will determine if a circulating brain protein, glial fibrillary acidic protein (GFAP), can serve as a rapid measure of brain injury and how well the cooling therapy is protecting the brain. Development of this novel approach would: 1) fill an immediate clinical void; 2) take advantage of the large investment already made in the NIH clinical trial; 3) provide early information on outcomes for families using a simple blood test and 4) guide clinicians to the best therapy to protect the brain in these ill infants.