Biomarkers of Neonatal Encephalopathy in a Nonhuman Primate Model

描述（由申请方提供）：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活产婴儿，并导致全球23%的新生儿死亡。治疗性低温降低了死亡和神经发育障碍的结局，但仅降低了约15%，因此50%受影响的治疗婴儿的结局仍然很差。准确反映脑损伤程度、损伤的时间和演变以及对治疗的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有永久性后遗症风险的婴儿;可能受益于干预的婴儿和治疗无效的婴儿;并将识别在特定治疗的治疗窗口内的婴儿。这些生物标志物对研究也很重要，因为它们可以准确识别高危婴儿， 降低入组受试者之间的变异性，从而减少充分把握度研究所需的患者数量。我们已经开发了一种非人灵长类动物模型的围产期窒息，其中脑损伤是由封闭的脐带出生前。我们的非人灵长类动物模型提供了一个无与伦比的机会来评估定时损伤后的循环和排泄代谢物和蛋白质，并研究脑损伤演变的结构生物标志物。将确定对治疗性低温的反应，并将潜在的生物标志物与神经发育结果相关联。最后，在尸检时，这些临床信息可以与病理结果相关联。我们假设，通过结合连续的代谢组学，蛋白质组学和结构评估，我们将开发一个评估小组缺氧缺血性脑病（HIE），将具有高灵敏度和特异性，诊断早期疾病的严重程度，预后，并可能对治疗性低温与长期神经发育状态作为最终结果。利用猕猴nemestrina模型的HIE，我们将开发：1）敏感和特异性诊断急性脑损伤严重程度的早期生物标志物。为了确保分类的准确性，我们将使用神经行为和结构2）HIE的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的顺序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;以及3）我们将开发生物标志物，以预测个人对治疗性低温的反应。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标记来推进该领域。

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.