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率和发病率的重要原因，因此它是一个重要的公共卫生问题。缺氧缺血性脑病是大多数儿童心脏骤停后神经系统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，是新疗法的重要靶点。我们的长期研究目标是阐明儿童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，在实验性儿童心脏窒息性骤停后，细胞色素P450的血管收缩和血管扩张的二十烷类代谢产物的平衡被扰乱，有利于血管收缩。此外，在我们的儿童窒息性心脏骤停模型中，抑制血管收缩性类二十烷的产生可防止皮质灌注不足并改善神经系统预后。本项目的目标是阐明细胞色素P450 4A/4F和2C/2J的类二十烷代谢产物在儿童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)明确血管收缩剂类二十烷在小儿心脏骤停后脑血流失调和神经变性中的作用；2)明确血管舒张剂类二十烷在小儿心脏骤停后脑血流正常化和神经保护中的作用；3)确定抑制类二十烷诱导的血管收缩和增强类二十烷诱导的血管舒张是否能改善小儿心脏骤停后的神经预后。我们提出创新的方法来评估神经血管单位从血管和神经元的角度，从分子到全球水平。我们已经组建了一个专家合作团队，包括(1)使用综合脂质组学方法的质谱分析，(2)通过动脉自旋标记磁共振成像评估脑血流，(3)通过双光子显微镜进行体内皮层微循环可视化的细胞成像，以及(4)心脏骤停的结果动物模型。如果这些血管和神经元双重靶向治疗可以减少小儿窒息性心脏骤停后继发性神经元损伤并改善预后，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

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.