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: 8520911
• 负责人: Sandra E Juul
• 金额: $ 65.05万
• 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/8520911
• 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; Encephalopathies; Enrollment; Ensure; Evaluation; Evolution; Family; Gold; Hour; Human; Individual; Infant; Infant Care; Injury; Intervention; Ischemic-Hypoxic Encephalopathy; Laboratories; Lactic acid; Macaca; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mental Retardation; Modeling; Neonatal; 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; functional outcomes; human disease; improved; infant outcome; intellectual and developmental disability; metabolomics; natural hypothermia; neonatal death; neonatal hypoxic-ischemic brain injury; neonate; neurobehavioral; nonhuman primate; novel; outcome forecast; protein metabolite; psychologic; public health relevance; response; response to injury

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）：在美国和全球范围内，缺氧 - 缺血性脑损伤仍然是一个重大问题，影响了美国的3-5/1000名活生生婴儿，并且在全球造成了新生儿死亡的23％。治疗性体温过低会降低死亡和神经发育障碍的结局，但仅降低了约15％，因此50％受影响的，治疗的婴儿的结果仍然很差。准确反映脑损伤程度的生物标志物损伤的时机和进化以及对治疗的反应是这些患者和研究的临床管理。理想的生物标志物将区分不需要常见后遗症患者的婴儿。可能受益于徒劳的人的干预措施的婴儿；并将确定在治疗窗口内进行特定治疗的婴儿。这样的生物标志物对于研究也很重要，因为它们将允许准确鉴定处于危险的婴儿， 降低注册受试者的变异性，从而减少了足够动力研究所需的患者人数。我们已经开发了一种非人类灵长类动物模型的围产期窒息模型，其中通过脐带在出生前的遮挡引起了脑损伤。我们的非人类灵长类动物模型提供了无与伦比的机会，可以在定时损伤后评估循环和排泄的代谢物和蛋白质，并随着脑损伤的发展研究结构生物标志物。将确定对治疗性体温过低的反应，潜在的生物标志物将与神经发育结局相关。最后，在尸检时，该临床信息可以与病理结局相关。 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.使用猕猴的Nemestrina模型，我们将开发：1）急性脑损伤严重程度的敏感和特定的诊断早期生物标志物。为了确保分类的准确性，我们将使用神经行为和结构性（MRI和死灵）在6个月大的情况下作为金标准； 2）使用蛋白质组，代谢组，MRI和MRS的顺序评估，将HIE长期结局的早期预后生物标志物与长期结构和功能结果相关联，将单个急性反应与损伤相关； 3）我们将开发生物标志物，以预测一个人对治疗性体温过低的反应。这项研究的结果将直接适用于两种临床实践，也将通过定义可用于研究目的的生物标志来推进该领域。