Sex differences in brain injury following pediatric cardiac arrest

描述（由申请人提供）：小儿心脏骤停是一种常见的和破坏性的条件，仍然知之甚少。死亡率极高，脑损伤是最常见的死亡原因。在过去的50年里，大多数关于心脏骤停的研究都集中在提高自主循环恢复率（ROSC）上，取得了显著进展，提高了生存率。然而，如果没有干预措施来尽量减少器官损伤，与我们改进的复苏实践相关的长期健康问题就会增加。这被称为心脏骤停后综合征，主要包括长期的神经功能缺损。事实上，一些干预措施在改善ROSC方面很有用，但在改善长期结果方面没有显示出益处。已经有许多在成年动物中进行的心脏骤停的临床前转化研究，证明了各种药物干预可以改善全脑缺血后的神经元存活。然而，到目前为止，由于模型稀缺，儿科心脏骤停的研究很少。在目前的提案中，我们描述了第一个儿科心脏骤停模型，利用小鼠研究心脏骤停对神经元存活的影响，并测试新的治疗方法。成人流行病学研究表明，与男性相比，女性在CA后的结局更好。在成年动物模型中进行的大量实验研究已经概括了这一临床数据，表明雌性动物在脑缺血后表现出的脑损伤明显少于雄性动物。在实验性成年动物中观察到的性别差异几乎可以完全由雌性动物中的高水平雌激素解释，因为去除内源性性类固醇（卵巢切除术）会使雌性脑损伤增加至雄性水平，而雌激素替代会使雌性损伤恢复至完整动物水平。毫不奇怪，我们没有观察到儿科小鼠缺血性损伤的性别差异，这与雄性和雌性动物的低雌激素青春期前状态一致。有趣的是，当外源性给予雌激素时，我们观察到对雌激素神经保护作用的反应存在显著的性别差异。我们观察到，在CA/CPR后的临床相关时间点（30分钟）给予单次静脉内雌激素剂量对女性大脑提供保护，而对男性大脑没有影响。因此，目前的建议的目的是为了进一步表征我们的新的儿科心脏骤停模型，并开始阐明在这个发育阶段观察到的性二态雌激素神经保护的分子机制。因此，我们将1）确定雌激素在确定小儿心脏骤停后神经元损伤中的作用，2）确定雌激素受体α和β（ERα和ER β）在雌激素神经保护中的相对作用。3)最后，明确雌激素在儿童心脏骤停中神经保护作用的分子机制。

DESCRIPTION (provided by applicant): Pediatric cardiac arrest is a common and devastating condition which remains poorly understood. Mortality rates are extremely high and brain injury is the most common cause of death. The majority of research regarding cardiac arrest over the past 50 years has focused on improving rates of return of spontaneous circulation (ROSC), with significant progress leading to increased survival rates. However, without interventions to minimize organ injury, there is an increase in long-term health issues associated with our improved resuscitation practices. This has been termed the post-cardiac arrest syndrome, consisting predominantly of long-term neurological deficits. Indeed, several interventions that have been useful in improving ROSC, have not shown benefit in improving long term outcome. There have been numerous pre- clinical translational studies of cardiac arrest in adult animals demonstrating various pharmacological interventions to improve neuronal survival following global cerebral ischemia. However, to date, there are very few studies in pediatric cardiac arrest, as models are scarce. In the current proposal, we describe the first pediatric cardiac arrest model utilizing mice to study the effects of cardiac arrest on neuronal survival and test new therapies. Epidemiologic studies in adults have suggested that females have better outcomes after CA when compared to males. Numerous experimental studies in adult animal models have recapitulated this clinical data, showing that female animals exhibit significantly less brain injury following cerebral ischemia than males. The sex difference observed in experimental adult animals can be nearly completely explained by the high levels of estrogen in female animals, as removal of endogenous sex steroids (ovariectomy) increases female brain injury to male levels and estrogen replacement returns female injury to intact animal levels. Not surprisingly, we did not observe a gender difference in ischemic injury in pediatric mice, consistent with pre- pubertal state of low estrogen in both male and female animals. Interestingly, when estrogen is exogenously administered we observe a remarkable sex-difference in response to estrogen neuroprotection. We observed that a single intravenous estrogen dose administered at a clinically relevant time point following CA/CPR (30 min) provides protection to the female brain, while having no effect in the male brain. Therefore, the aims of the current proposal are designed to further characterize our novel pediatric cardiac arrest model and begin to elucidate the molecular mechanisms of sexually dimorphic estrogen neuroprotection observed at this developmental stage. Therefore, we will 1) establish the role of estrogen in determining neuronal injury following pediatric cardiac arrest and 2) determine the relative contribution of estrogen receptors alpha and beta (ERα and ERß) in estrogen neuroprotection. 3) Finally, determine the molecular mechanism of estrogen neuroprotection in pediatric cardiac arrest.