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（由申请人提供）：缺氧缺血性脑损伤仍然是美国和全球的一个重大问题，影响美国 3-5/1000 的活产婴儿，并导致全球 23% 的新生儿死亡。治疗性低温可降低死亡和神经发育障碍的结果，但仅降低约 15%，因此 50% 受影响的接受治疗的婴儿的结果仍然较差。这些患者的临床管理和研究迫切需要准确反映脑损伤程度、损伤发生时间和演变以及对治疗反应的生物标志物。理想的生物标志物能够将不需要治疗的婴儿与有永久性后遗症风险的婴儿区分开来；可能受益于治疗无效的婴儿的干预；并将识别处于特定治疗治疗窗口内的婴儿。此类生物标志物对于研究也很重要，因为它们可以准确识别有风险的婴儿， 减少入组受试者之间的变异性，从而减少充分有力的研究所需的患者数量。我们开发了一种围产期窒息的非人类灵长类动物模型，其中出生前脐带闭塞引起脑损伤。我们的非人类灵长类动物模型提供了无与伦比的机会来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志物。对低温治疗的反应将被确定，潜在的生物标志物将与神经发育结果相关。最后，在尸检时，该临床信息可以与病理结果相关联。我们假设，通过结合顺序代谢组学、蛋白质组学和结构评估，我们将开发一个缺氧缺血性脑病 (HIE) 评估小组，该小组将以高灵敏度和特异性诊断疾病的早期严重程度、预后以及对低温治疗的可能反应以长期神经发育状态作为最终结果。使用 HIE 的猕猴线虫模型，我们将开发：1）急性脑损伤严重程度的敏感且特异的诊断早期生物标志物。为了确保分类的准确性，我们将使用 6 个月龄时的神经行为和结构（MRI 和尸检）结果作为金标准； 2) HIE长期结果的早期预后生物标志物，使用蛋白质组、代谢组、MRI和MRS的连续评估，将个体对损伤的急性反应与长期结构和功能结果相关联； 3）我们将开发生物标志物来预测个体对低温治疗的反应。这项研究的结果将直接适用于临床实践，并且还将通过定义可用于研究目的的生物标记来推进该领域的发展。