Biomarkers of Neonatal Encephalopathy in a Nonhuman Primate Model

描述（由申请人提供）：缺氧缺血性脑损伤在美国和全球仍然是一个重要的问题，影响着美国3-5/1000的活产婴儿，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果，但仅降低了约15%，因此50%的受影响治疗婴儿的结果仍然很差。准确反映脑损伤程度、损伤时间和进化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至关重要。理想的生物标志物可以区分不需要治疗的婴儿和有永久后遗症风险的婴儿；那些治疗无效的婴儿可能会从干预中受益；并识别出处于特定治疗窗口期的婴儿。这些生物标记物对研究也很重要，因为它们可以准确识别有风险的婴儿，

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.