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

描述(申请人提供)：儿科心脏骤停仍然是死亡率和发病率的一个重要原因，因此是一个重要的公共卫生问题。缺氧缺血性脑病是大多数儿科患者心脏骤停后神经功能恢复的限制因素。脑血流障碍可能进一步导致心脏骤停后的神经病理损害，并成为新疗法的重要靶点。我们的长期研究目标是阐明儿童窒息心脏骤停后病理性脑血流失调的关键血管通路，并开发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，在儿童实验性心脏窒息后，细胞色素P450的血管收缩和血管扩张剂二十烷基类代谢物的平衡被破坏，有利于血管收缩。此外，在我们的儿童窒息心脏骤停模型中，抑制血管收缩类二十烷酸的产生可以防止皮质低灌流和改善神经预后。本项目的目标是阐明细胞色素P450 4A/4F和2C/2J的二十烷基类代谢物在儿童心脏骤停后引起脑血流紊乱和神经毒性的机制，并开发针对这些途径的创新疗法。我们建议1)明确血管收缩因子二十烷类化合物在儿童心脏骤停后脑血流失调和神经变性中的作用，2)确定扩张性二十烷类化合物在儿童心脏骤停后脑血流正常化和神经保护中的作用，以及3)确定抑制二十烷类化合物诱导的血管收缩和增强二十烷类化合物诱导的血管扩张是否改善儿童心脏骤停后的神经预后。我们提出了从血管和神经元的角度，从分子到全球水平来评估神经血管单位的创新方法。我们已经组建了一个合作的专家团队，其研究领域包括：(I)使用综合脂质体学方法的质谱学专家；(Ii)通过动脉自旋标记磁共振成像进行脑血流评估的专家；(Iii)通过双光子显微镜进行皮质微循环活体可视化的细胞成像；以及(Iv)心脏骤停的结局动物模型。如果这些双重的血管和神经元靶向治疗减少继发性神经元损伤并改善儿童窒息心脏骤停后的预后，那么这种新方法的临床翻译将对婴儿和儿童产生重大影响。 心脏骤停的患者。

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.