Gender-Specific Treatment of Pediatric Cardiac Arrest

描述（由申请人提供）：婴儿和儿童的心肺骤停仍然是发病率和死亡率的重要原因。影响心肺骤停幸存者预后的主要因素是缺氧缺血性脑病引起的神经系统后遗症，不幸的是，没有干预措施可以逆转缺氧缺血性脑病的细胞后果。一个临床相关的大鼠出生后第17天的儿童窒息性心脏骤停模型已经开发出来，该模型具有模仿人类使用的指导方针的侵入性生理监测和复苏能力，生化和细胞评估，以及急性和长期功能结果评估，具有应用康复策略的潜力。初步数据显示，在幼年大鼠窒息后损伤的大脑和培养的神经元中，谷胱甘肽代谢和凋亡级联的激活存在关键的性别差异，这意味着导致神经变性和最终细胞死亡和存活的途径可能在性别之间存在差异。这是至关重要的，因为在今天，婴儿和儿童在心肺骤停后的治疗是相似的，无论他们是男孩还是女孩，两种性别都受到这种临床实体的影响，比例相似。据我们所知，性别在性成熟前心肺骤停后缺氧缺血性脑病的病理生物学中的影响尚未得到彻底解决。利用这种幼年大鼠窒息性心肺骤停的体内模型，结合平行的体外研究，将验证全球低氧缺血/再灌注启动性别特异性细胞死亡途径和可逆性神经损伤的假设。特定目的旨在确定神经保护是否可以通过专门针对谷胱甘肽耗竭和细胞凋亡的新疗法来实现，以及治疗效果是否与性别有关。婴儿和儿童在心肺骤停后的悲惨结局以及由此产生的社会影响需要在临床相关模型中进行严格的临床前测试。本研究方案的主要目的是确定有效的、有性别差异的婴儿和儿童心肺骤停后预后改善临床试验和有性别差异的治疗策略，为婴儿和儿童心肺骤停后预后改善临床试验奠定基础。

DESCRIPTION (provided by applicant): Cardiopulmonary arrest in infants and children remains a significant cause of morbidity and mortality. The principle factor influencing outcome in survivors of cardiopulmonary arrest is the neurologic sequelae resulting from hypoxic-ischemic encephalopathy, unfortunately, there are no interventions to reverse the cellular consequences of hypoxic-ischemic encephalopathy. A clinically relevant model of pediatric asphyxial cardiac arrest in postnatal day 17 rats has been developed that has the capacity for invasive physiologic monitoring and resuscitation that mimics guidelines used in humans, biochemical and cellular assessment, and acute and long-term functional outcome assessment with the potential for application of rehabilitation strategies. Preliminary data show key gender differences in glutathione metabolism and activation of apoptotic cascades in the injured brains of juvenile rats after asphyxia and neurons in culture, implying that pathways leading to neurodegeneration and ultimate cell death and survival may be different between sexes. This is of paramount importance because in the present day infants and children are treated similarly after cardiopulmonary arrest whether they are boys or girls, and both genders are affected by this clinical entity in similar proportions. To our knowledge the influence of gender in the pathobiology of hypoxic-ischemic encephalopathy after cardiopulmonary arrest prior to sexual maturation has not been thoroughly addressed. Using this in vivo model of asphyxial cardiopulmonary arrest in juvenile rats, coupled with parallel in vitro studies, the hypothesis that global hypoxemia-ischemia/reperfusion initiates gender specific cell death pathways and reversible neurological impairments will be tested. Specific Aims are designed to determine whether neuroprotection can be achieved using novel therapies specifically targeting glutathione depletion and apoptosis, and whether therapeutic efficacy is gender-dependent. Dismal outcomes seen in infants and children after cardiopulmonary arrest and the resultant societal impact warrant rigorous pre-clinical testing in a clinically relevant model. The primary objective of this research proposal is to identify efficacious and gender-specific the clinical trials designed to improve outcome in infants and children after cardiopulmonary arrest and gender-specific, therapeutic strategies, to serve as the foundation for clinical trials designed to improve outcome in infants and children after cardiopulmonary arrest.