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后遗症，不幸的是，没有干预措施逆转缺氧缺血性脑病的细胞后果。一种临床相关的出生后第17天大鼠窒息心脏骤停的模型已经被开发出来，该模型具有模拟人类使用的指南的侵入性生理监测和复苏能力，生化和细胞评估，以及具有应用康复策略的可能性的急性和长期功能结果评估。初步数据显示，在幼年大鼠窒息后损伤的脑和培养的神经元中，谷胱甘肽代谢和凋亡级联激活的关键性别差异，意味着导致神经退化和最终细胞死亡和存活的途径可能在性别之间不同。这一点至关重要，因为在当今，婴儿和儿童在心肺骤停后受到类似的对待，无论他们是男孩还是女孩，而且男女都受到这一临床实体的类似比例的影响。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还没有得到彻底的解决。利用这种幼年大鼠窒息心肺骤停的体内模型，再加上平行的体外研究，将检验全球缺氧-缺血/再灌注引发性别特定的细胞死亡途径和可逆神经损伤的假设。具体目的是确定是否可以使用专门针对谷胱甘肽耗竭和细胞凋亡的新疗法来实现神经保护，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。这项研究建议的主要目标是确定有效和针对性别的临床试验，旨在改善婴儿和儿童心肺骤停后的结局和针对性别的治疗策略，作为旨在改善婴儿和儿童心肺骤停后结局的临床试验的基础。

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.