Sex Steroids and Brain Outcome from Cardiac Arrest/Cardiopulmonary Resuscitation

性类固醇和心脏骤停/心肺复苏的脑结果

• 批准号: 7755865
• 负责人: RICHARD J TRAYSTMAN
• 金额: $ 33.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755865
• 关键词: Androgen Receptor; Androgens; Behavioral; Brain; Brain Injuries; CARTPT gene; Candidate Disease Gene; Cardiopulmonary Resuscitation; Cardiovascular Diseases; Castration; Cerebral Ischemia; Cerebrovascular Disorders; Cerebrum; Cessation of life; Clinical; Data; Estradiol; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Evaluation; Event; Female; Flutamide; Funding; Gonadal Steroid Hormones; Heart Arrest; Human; In Vitro; Incidence; Individual; Injury; Ischemia; Knockout Mice; Life; MAPK1 gene; Men' s Role; Mus; Neurologic; Neuronal Injury; Neurons; Neuropeptides; Neuroprotective Agents; Outcome; Pathway interactions; Patients; Performance; Phosphorylation; Phosphotransferases; Play; Recovery of Function; Research; Risk; Risk Factors; Rodent; Role; Signal Transduction; Stanolone; Techniques; Testing; Testosterone; Woman; Work; brain shape; cell injury; cocaine- and amphetamine-regulated transcript protein; extracellular; improved; in vivo; injured; male; men; mouse model; neuroprotection; neuropsychological; novel; overexpression; receptor; response; sex; sudden cardiac death

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.

描述（由申请人提供）：尽管对心脏骤停/心肺复苏（CA/CPR）进行了50年的研究，但临床结局仍然很差。只有5%的CA患者成功复苏，恢复正常的生活，其余95%的患者仍然普遍存在神经心理缺陷。CA/CPR结果仍然不佳的一个原因是细胞损伤机制和神经保护靶点尚未得到很好的阐明。女性患心血管疾病的风险低于男性，但脑缺血事件在两性中都有发生。雌激素在人类中的作用是有争议的;然而，我们在过去的资助期间证明，CA/CPR后雌性小鼠的结果比雄性小鼠好。我们现在关注的是雌二醇在CA/CPR中发挥神经保护作用的潜在转录机制。使用微阵列技术，我们确定了在缺血条件下雌激素诱导/抑制的候选基因。一个挑衅性的候选者，神经肽可卡因和安非他明调节的转录物（CART）是由脑缺血强烈诱导，并提供强大的神经保护。我们建议确定CART是否是雌二醇减少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，一种有可能加剧CA/CPR脑损伤的性类固醇。我们的初步数据表明，睾丸激素增加和去势减少CA/CPR后神经元损伤，我们假设雄激素信号通过其同源受体协调神经元缺血性死亡。因此，这项建议将集中在新的机制，男性和女性性类固醇形状CA/CPR后的大脑结果。目的1确定雌二醇是否以区域特异性方式增强CA/CPR后CART表达并抑制ERK激活。目的2确定CART保护是否需要通过雌激素受体β信号传导。目的3确定雄激素是否在CA/CPR后的神经病理和功能恢复中起重要作用。最后，目的4确定雄激素受体是否对雄激素如何增强停搏后脑损伤至关重要。