Sex Steroids and Brain Outcome from Cardiac Arrest/Cardiopulmonary Resuscitation

描述(由申请人提供)：尽管关于心脏骤停/心肺复苏(CA/CPR)的研究已有50年，但临床结果仍然很差。只有5%的CA患者成功复苏，恢复正常的生产生活，其余95%的患者仍然普遍存在神经心理缺陷。CA/CPR治疗效果不佳的原因之一是细胞损伤的机制和神经保护的靶点尚未阐明。女性患心血管疾病的风险比男性低，但脑缺血事件在两性中都会发生。雌激素在人类中的作用是有争议的；然而，在过去的资助期间，我们证明了雌性小鼠在CA/CPR后比雄性小鼠有更好的结果。我们现在关注的是雌激素在CA/CPR中发挥神经保护作用的潜在转录机制。利用微阵列技术，我们确定了在缺血条件下雌激素诱导/抑制的候选基因。神经肽可卡因和苯丙胺调节转录本(CART)是一种具有刺激性的候选基因，由脑缺血强烈诱导，并提供强大的神经保护作用。我们建议确定CART是否是雌激素减轻CA/CPR后神经元损伤的重要机制，以及CART是否通过细胞外调节激酶(ERK)途径发挥其神经保护作用。虽然大多数研究都集中在了解雌二醇在缺血中的作用，但雄激素在缺血敏感性中的作用尚不清楚。我们建议研究睾酮，一种可能加重CA/CPR脑损伤的性类固醇。我们的初步数据表明，CA/CPR后睾酮增加，去势减少神经元损伤，我们假设雄激素通过其同源受体发出信号，协调神经元缺血性死亡。因此，这项建议将侧重于男性和女性性激素如何影响CA/CPR后脑部结果的新机制。目的1确定雌激素是否以区域特异性的方式增强CA/CPR后CART的表达并抑制ERK的激活。目的2确定CART保护是否需要通过雌激素受体β信号。目的3确定雄激素在CA/CPR后神经病理和功能恢复中是否起重要作用。最后，目标4确定雄激素受体是否在雄激素如何增强停搏后脑损伤中起关键作用。

DESCRIPTION (provided by applicant): Despite five decades of research concerning cardiac arrest/cardiopulmonary resuscitation (CA/CPR), clinical outcome remains poor. Only 5% of individuals who suffer CA are successfully resuscitated to the extent that they return to normal, productive lives, and neuropsychological deficiencies remain prevalent in the remaining 95% of patients. One reason why outcome from CA/CPR remains poor is that mechanisms of cell injury and targets for neuroprotection have been poorly elucidated. Women are at lower risk than men for cardiovascular disease yet cerebral ischemic events occur in both sexes. The role of estrogens in humans is controversial; however, we demonstrated in the past funding period that female mice have better outcome than males after CA/CPR. We now focus on potential transcriptional mechanisms by which estradiol exerts its neuroprotective action in CA/CPR. Using a microarray technique, we identified gene candidates that are induced/suppressed by estrogen under ischemic conditions. One provocative candidate, the neuropeptide cocaine and amphetamine regulated transcript (CART) is strongly induced by cerebral ischemia and provides robust neuroprotection. We propose to determine if CART is an important mechanism by which estradiol reduces neuronal injury after CA/CPR and whether CART exerts its neuroprotective effects via the extracellular regulated kinase (ERK) pathway. While most research has focused on understanding the role of estradiol in ischemia, the role of androgens in ischemic sensitivity is unknown. We propose to study testosterone, a sex steroid with potential to exacerbate brain injury from CA/CPR. Our preliminary data suggests that testosterone increases and castration decreases neuronal injury after CA/CPR, and we hypothesize that androgens signal through their cognate receptor to orchestrate neuronal ischemic death. Thus, this proposal will focus on novel mechanisms by which male and female sex steroids shape brain outcome after CA/CPR. Aim 1 determines if estradiol enhances CART expression and suppresses ERK activation after CA/CPR in a region-specific manner. Aim 2 determines if CART protection requires signaling via estrogen receptor beta. Aim 3 determines if androgens play an important role in neuropathological and functional recovery after CA/CPR. Finally, Aim 4 determines if the androgen receptor is essential to how androgen enhances post arrest brain injury.