Sex differences in brain injury following pediatric cardiac arrest

描述(由申请人提供)：儿童心脏骤停是一种常见的破坏性疾病，目前仍知之甚少。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的返回率(ROSC)上，并取得了显著的进展，从而提高了存活率。然而，如果没有干预措施将器官损伤降至最低，与我们改进的复苏做法相关的长期健康问题会增加。这被称为心脏骤停后综合征，主要由长期的神经功能障碍组成。事实上，几种干预措施在改善ROSC方面很有用，但在改善长期结果方面并没有显示出好处。已有大量关于成年动物心脏骤停的临床前翻译研究，展示了各种药物干预措施，以改善全脑缺血后神经元的存活。然而，到目前为止，关于儿童心脏骤停的研究很少，因为模型很少。在目前的提案中，我们描述了第一个儿童心脏骤停模型，利用小鼠来研究心脏骤停对神经元存活的影响并测试新的治疗方法。在成人中的流行病学研究表明，与男性相比，女性CA后的结果更好。许多成年动物模型的实验研究都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低于雄性动物。在实验成年动物中观察到的性别差异可以几乎完全用雌性动物体内高水平的雌激素来解释，因为去除内源性类固醇(卵巢切除)会增加女性大脑损伤到男性水平，而雌激素替代使女性损伤恢复到完整的动物水平。毫不奇怪，我们在儿科小鼠中没有观察到缺血性损伤的性别差异，这与雄性和雌性动物的青春期前低雌激素状态一致。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单次静脉注射雌激素剂量(30分钟)对女性大脑提供保护，而对男性大脑没有影响。因此，本提案的目的是进一步描述我们新的儿科心脏骤停模型，并开始阐明在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)确定雌激素在确定儿童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ERç)在雌激素神经保护中的相对贡献。3)探讨儿童心脏骤停时雌激素神经保护的分子机制。

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.