Early Biomarkers in Neonatal Brain Injury

新生儿脑损伤的早期生物标志物

• 批准号: 8635230
• 负责人: Sonia L Bonifacio
• 金额: $ 19.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635230
• 关键词: Address; Age; Anatomy; Animal Model; Biological Markers; Birth; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Caring; Cell Death; Cerebrum; Cessation of life; Clinical; Clinical Trials; Clinical Trials Design; Complex; Data; Development; Diffusion; Educational workshop; Electroencephalography; Encephalopathies; Enrollment; Erythropoietin; Event; Evolution; Funding; Future; Hour; Human; Hypoxia; Image; Imaging Techniques; Impaired cognition; Injury; Intervention; Intervention Trial; Ischemic-Hypoxic Encephalopathy; K-Series Research Career Programs; Life; Live Birth; Location; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mentors; Meta-Analysis; Metabolic; Metabolism; Mitochondria; Modality; Monitor; Morbidity - disease rate; N-acetylaspartate; National Institute of Child Health and Human Development; Neonatal; Neonatal Brain Injury; Neuroprotective Agents; Outcome; Parents; Pathway interactions; Patient Selection; Pattern; Phase; Prognostic Marker; Randomized Clinical Trials; Reperfusion Therapy; Research; Risk; Scanning; Secondary to; Seizures; Severities; Techniques; Therapeutic; Therapeutic Agents; Time; Training; United States National Institutes of Health; brain metabolism; cohort; disability; follow-up; improved; injury and repair; motor impairment; natural hypothermia; neonatal hypoxic-ischemic brain injury; neonate; neurogenesis; neurophysiology; neuroprotection; pre-clinical; prognostic; public health relevance; randomized trial; repaired; response; success

DESCRIPTION (provided by applicant): Hypoxic-Ischemic Encephalopathy (HIE) in neonates occurs in 1-6/1000 live births and results in significant morbidity and mortality1. Therapeutic hypothermia is the first treatment to have demonstrated success in reducing the risk of death or severe disability, although it is not completely efficacious with death or adverse neurodevelopmental outcome in 40-55% of neonates in randomized trials 2-7. Following a hypoxic-ischemic insult, there are different phases of cerebral injury during which timely administration of phase-specific therapeutic agents in addition to hypothermia can provide additional neuroprotection and promote repair in experimental models8. An exciting therapeutic emerging in pilot clinical trials is erythropoietin (EPO). EPO enhances neurogenesis and repair and treatment can be effective even when delayed till 24 hours after injury 9. Unfortunately, early markers that identify the phase of injury and repair are not yet well understood in human neonates and the ascertainment of useful developmental outcomes require, at minimum 18 months of follow up. Potential biomarkers in humans include real-time measures of brain function (EEG), metabolism (1H-MRS - lactate, creative, N-acetyl aspartate) and evidence of parenchymal brain injury (MRI) 10. We propose that these biomarkers can assist in interpreting the timing and severity of injury, provide information on the mechanisms of injury, and can delineate those neonates who could benefit from additional neuroprotection. The importance of the identification of these at-risk neonates for enrollment in further trials of neuroprotectants ws supported by an NICHD workshop 11. During this career development award I will study the ability of early and continuous monitoring of brain function and advanced imaging techniques to evaluate brain metabolism and identify neonates that may benefit from neuroprotective agents and strategies. Currently, MRI is done late, from 5-12 days after birth, to provide prognostic information for parents. However, if done earlier, in conjunction with other biological markers, imaging may be able to rationally guide adjunctive therapies that are now being considered for clinical trials. This proposal will add the unique ability to provide continuous bedside monitoring and early advanced imaging to an ongoing NIH funded longitudinal study of specialized MRI techniques in prognosticating outcome in neonates with HIE. Use of continuous EEG and serial MRI will allow us to visualize the phases of injury, the cerebral response to therapy and to understand the appropriate windows for intervention. I will obtain specific training in quantitativ advanced imaging, neurophysiology, analysis of complex longitudinal data and in clinical trial design and implementation. I have assembled a multi-disciplinary mentoring team and comprehensive training plan will guide me in carrying out the research proposed and enable me to become a leader in neonatal neurocritical care and neuroprotective intervention trials, with successful attainment of an R01.

描述（由申请人提供）：新生儿中的缺氧 - 缺血性脑病（HIE）发生在1-6/1000的活产中，并导致显着的发病率和死亡率1。治疗性体温过低是第一种在降低死亡或严重残疾的风险方面取得成功的治疗方法，尽管在40-55％的新生儿中，在随机试验中，在2-7的随机试验中，它并不完全有效或不良神经发育结果。在缺氧缺血性损伤之后，除了体温过低外，脑损伤的阶段不同，在此期间，及时给予特异性治疗剂，可以提供额外的神经保护作用，并在实验模型中促进修复8。在试验临床试验中出现的令人兴奋的治疗方法是促红细胞生成素（EPO）。即使延迟到受伤后24小时，EPO可以增强神经发生，修复和治疗也可以有效。不幸的是，在人类新生儿中尚未对确定损伤和修复阶段的早期标记尚不清楚，并且在至少18个月的随访中确定了有用的发育结果。人类中的潜在生物标志物包括脑功能的实时测量（EEG），代谢（1H-MR-乳酸，创造性，n-乙酰基本基）和实质脑损伤的证据（MRI）10。我们建议这些生物标志物可以帮助造成伤害的时间和损害的信息，从而使这些人造成这些伤害的信息，从而使这些人造成了损害的损害，并可以使这些疾病造成这些疾病的损害，并且可以使这些疾病造成这些疾病的差异。 NICHD研讨会11支​​持的神经保护剂WS的进一步试验的鉴定，在此职业发展奖中，我将研究对脑功能和高级成像技术的早期监测能力，以评估脑部代谢并确定可能受益于神经保护药物和策略。目前，从出生后5-12天开始，MRI迟到，为父母提供预后信息。但是，如果较早完成，则与其他生物标记物结合使用，成像可能能够合理地指导辅助疗法，这些疗法现在正在考虑用于临床试验。该建议将增加提供连续床头监控的独特能力 以及正在进行的NIH进行的早期成像资助了专门的MRI技术的纵向研究，以预测与HIE的新生儿的预测结果。使用连续的脑电图和串行MRI将使我们能够可视化受伤的阶段，对治疗的大脑反应，并了解适当的干预窗口。我将在定量高级成像，神经生理学，复杂纵向数据以及临床试验设计和实施方面进行特定的培训。我已经组建了一个多学科指导团队，全面的培训计划将指导我进行拟议的研究，并使我能够成功获得R01，使我成为新生儿神经护理和神经保护干预试验的领导者。