Biomarkers of Neonatal Encephalopathy in a Nonhuman Primate Model

非人灵长类动物模型中新生儿脑病的生物标志物

• 批准号: 9105736
• 负责人: Sandra E Juul
• 金额: $ 64.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105736
• 关键词: Acute; Acute Brain Injuries; Affect; Age; Age-Months; Animal Model; Animals; Apgar Score; Asphyxia Neonatorum; Autopsy; Behavioral; Biochemical; Biological Markers; Birth; Blood; Brain; Brain Injuries; Calibration; Cerebral Palsy; Cessation of life; Characteristics; Clinical; Clinical Management; Clinical Trials; Clinical assessments; Development; Diagnosis; Diagnostic; Early Diagnosis; Enrollment; Ensure; Evaluation; Evolution; Family; Gold; Health; Hour; Human; Hypoxic-Ischemic Brain Injury; Individual; Infant; Infant Care; Injury; Intellectual functioning disability; Intervention; Laboratories; Lactic acid; Macaca; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mental Retardation; Modeling; Neurodevelopmental Disability; Neurodevelopmental Impairment; Newborn Infant; Outcome; Outcome Measure; Pathologic; Patients; Pre-Clinical Model; Prognostic Marker; Proteome; Proteomics; Qualifying; Randomized Controlled Trials; Research; Risk; Sensitivity and Specificity; Severities; Severity of illness; Specificity; Surrogate Markers; Therapeutic; Time; Translating; Umbilical cord structure; Urine; Validation; Writing; base; clinical practice; diagnostic biomarker; functional outcomes; human disease; improved; improved outcome; metabolome; metabolomics; natural hypothermia; neonatal death; neonatal encephalopathy; neonatal hypoxic-ischemic brain injury; neonate; neurobehavioral; nonhuman primate; novel; outcome forecast; potential biomarker; predicting response; predictive marker; protein metabolite; psychologic; response; response to injury; unnecessary treatment

DESCRIPTION (provided by applicant): Hypoxic-ischemic brain injury remains a significant problem in the US and globally, affecting 3-5/1000 liveborn infants in the US, and contributing to 23% of neonatal deaths globally. Therapeutic hypothermia decreases the outcomes of death and neurodevelopmental disability, but only by approximately 15%, so outcomes remain poor for 50% of affected, treated infants. Biomarkers that accurately reflect the degree of brain injury the timing and evolution of injury, and response to therapy are critically needed for clinical management of these patients and for research. Ideal biomarkers would differentiate infants who do not require treatment from those at risk of permanent sequelae; infants that might benefit from intervention from those for whom treatment is futile; and would identify infants who are within a therapeutic window for a specific treatment. Such biomarkers would also be important for research because they would allow for the accurate identification of at-risk infants, decreasing variability among enrolled subjects, thereby decreasing the numbers of patients required for adequately powered studies. We have developed a nonhuman primate model of perinatal asphyxia in which brain injury is induced by occlusion of the umbilical cord prior to birth. Our nonhuman primate model provides an unmatched opportunity to assess circulating and excreted metabolites and proteins after a timed injury, and to study structural biomarkers as brain injury evolves. The response to therapeutic hypothermia will be determined, and potential biomarkers will be correlated with neurodevelopmental outcomes. Finally, at necropsy, this clinical information can be correlated to pathologic outcomes. We hypothesize that by combining sequential metabolomic, proteomic, and structural assessments, we will develop an assessment panel for hypoxic ischemic encephalopathy (HIE) that will, with high sensitivity and specificity, diagnose early severity of illness, prognosis, and likely response to therapeutic hypothermia with long term neurodevelopmental status as a final outcome. Using a macaque nemestrina model of HIE we will develop: 1) Sensitive and specific diagnostic early biomarkers of severity of acute brain injury. To ensure accuracy of categorization, we will use neurobehavioral and structural (MRI and necropsy) outcomes at 6 months of age as a gold standard; 2) Early prognostic biomarkers of long term outcomes of HIE, using sequential evaluations of the proteome, metabolome, MRI and MRS to correlate individual acute response to injury with long-term structural and functional outcomes; and 3) We will develop biomarkers which predict an individual's response to therapeutic hypothermia. Results of this study will be directly applicable to both clinical practice, and will also advance the field by defining biomarkes that can be used for research purposes.

描述(申请人提供)：缺氧缺血性脑损伤在美国和全球仍然是一个严重的问题，在美国影响到3-5/1000名活产婴儿，占全球新生儿死亡的23%。治疗性低温降低了死亡和神经发育障碍的结局，但仅降低了大约15%，因此50%受影响的接受治疗的婴儿的结局仍然很差。准确反映脑损伤程度、损伤时间和演变以及对治疗反应的生物标志物对于这些患者的临床管理和研究是至关重要的。理想的生物标志物将区分不需要治疗的婴儿和那些有永久后遗症风险的婴儿；区分可能从干预中受益的婴儿和那些治疗无效的婴儿；并识别哪些婴儿处于特定治疗的治疗窗口内。这种生物标志物对研究也很重要，因为它们将允许准确识别高危婴儿， 减少受试者之间的变异性，从而减少足够动力的研究所需的患者数量。我们建立了一种围产期窒息的非人类灵长类动物模型，在该模型中，脑损伤是由出生前脐带闭塞引起的。我们的非人灵长类动物模型提供了一个无与伦比的机会，可以评估定时损伤后循环和排泄的代谢物和蛋白质，并研究脑损伤演变过程中的结构生物标记物。对治疗性低温的反应将被确定，潜在的生物标记物将与神经发育结果相关。最后，在尸检中，这些临床信息可以与病理结果相关联。我们假设，通过结合序贯代谢学、蛋白质组学和结构评估，我们将开发一个针对缺氧缺血性脑病(HIE)的评估小组，该小组将以高敏感度和特异度诊断疾病的早期严重程度、预后和可能对治疗低温的反应，并以长期神经发育状态作为最终结果。利用HIE恒河猴模型，我们将开发出：1)敏感和特异的急性脑损伤严重程度的早期诊断生物标志物。为了确保分类的准确性，我们将使用6个月大时的神经行为和结构(MRI和尸检)结果作为金标准；2)使用对蛋白质组、代谢组、MRI和MRS的顺序评估，对HIE的长期结果进行早期预后生物标记物的评估，以将个体对损伤的急性反应与长期结构和功能结果相关联；以及3)我们将开发预测个人对低温治疗的反应的生物标记物。这项研究的结果将直接适用于临床实践，并将通过定义可用于研究目的的生物标记物来推动该领域的发展。