CYP 450-mediated CBF Dysregulation and Neurotoxicity in Pediatric Cardiac Arrest

描述（由申请人提供）：儿童心脏骤停仍然是死亡和发病的重要原因，因此是一个重要的公共卫生问题。缺血性脑病是大多数儿童心脏骤停后神经功能完整恢复的限制因素。脑血流障碍可能进一步导致心脏骤停后的神经病理损伤，并代表新疗法的重要靶点。我们的长期研究目标是阐明小儿窒息性心脏骤停后病理性脑血流失调的关键血管通路，并制定预防脑血流失调和继发性神经元损伤的治疗策略。令人信服的初步数据表明，血管收缩和血管扩张类花生酸代谢物的细胞色素P450的平衡被打乱有利于血管收缩剂后，实验性小儿心脏窒息停止。此外，在我们的小儿窒息性心脏骤停模型中，抑制血管收缩性类花生酸的产生防止了皮质灌注不足并改善了神经学结果。该项目的目标是阐明细胞色素P450 4A/4F和2C/2 J的类花生酸代谢物在小儿心脏骤停后产生脑血流失调和神经毒性的机制，并开发针对这些途径的创新疗法。我们建议：1）确定血管收缩剂类花生酸在小儿心脏骤停后脑血流失调和神经变性中的作用，2）确定血管舒张类花生酸在小儿心脏骤停后脑血流正常化和神经保护中的作用，3）确定抑制类花生酸诱导的血管收缩和增强类花生酸诱导的血管舒张是否改善小儿心脏骤停后的神经结局。我们提出了创新的方法来评估从血管和神经元的角度来看，从分子到全球水平的神经血管单位。我们已经组建了一个合作小组的专家（i）质谱与专业知识，使用全面的脂质组学方法，（ii）脑血流评估动脉自旋标记磁共振成像，（iii）细胞成像在体内可视化的皮质微循环通过双光子显微镜，和（iv）结果动物模型的心脏骤停。如果这些双重血管和神经靶向治疗减少继发性神经元损伤并改善小儿窒息性心脏骤停后的结局，那么这种新方法的临床转化将对婴儿和儿童产生重大影响 心脏骤停的人

DESCRIPTION (provided by applicant): Pediatric cardiac arrest remains a significant cause of mortality and morbidity and thus it is an important public health problem. Hypoxic ischemic encephalopathy is the limiting factor for intact neurological recovery in a majority of pediatric patients after cardiac arrest. Cerebral blood flow disturbances may further contribute to neuropathological damage after cardiac arrest and represent an important target for novel therapies. Our long term research goal is to elucidate key vascular pathways involved in pathologic cerebral blood flow dysregulation after pediatric asphyxial cardiac arrest and to develop therapeutic strategies that prevent cerebral blood flow dysregulation and secondary neuronal damage. Compelling preliminary data suggest that the balance of vasoconstrictive and vasodilator eicosanoid metabolites of cytochrome P450 is disturbed in favor of vasoconstrictors after experimental pediatric cardiac asphyxial arrest. Furthermore, inhibiting the production of vasoconstrictive eicosanoids prevented the cortical hypoperfusion and improved neurological outcome in our pediatric asphyxial cardiac arrest model. The goal of this project is to elucidate mechanisms through which eicosanoid metabolites of cytochrome P450 4A/4F and 2C/2J produce cerebral blood flow dysregulation and neurotoxicity after pediatric cardiac arrest and to develop innovative therapies that target these pathways. We propose to 1) define the role of vasoconstrictor eicosanoids in cerebral blood flow dysregulation and neurodegeneration after pediatric cardiac arrest, 2) define the role of vasodilatatory eicosanoids in cerebral blood flow normalization and neuroprotection after pediatric cardiac arrest and 3) determine if inhibiting eicosanoid-induced vasoconstriction and enhancing eicosanoid- induced vasodilatation improves neurological outcome after pediatric cardiac arrest. We propose innovative approaches to assessing the neurovascular unit from both vascular and neuronal perspectives, from the molecular to the global level. We have assembled a collaborative team of experts in (i) mass spectrometry with expertise using a comprehensive lipidomic approach, (ii) cerebral blood flow assessment by arterial spin label magnetic resonance imaging, (iii) cell imaging for in vivo visualization of cortical microcirculation via two photon microscopy, and (iv) an outcome animal model of cardiac arrest. If these dual vascular- and neuronal-targeted therapies reduce secondary neuronal damage and improve outcome after pediatric asphyxial cardiac arrest, then clinical translation of this novel approach would be of significant impact for infants and children who suffer cardiac arrest.