Hypothermia and Gene Expression After Cardiac Arrest

心脏骤停后体温过低和基因表达

• 批准号: 6766771
• 负责人: Clifton W. Callaway
• 金额: $ 24.69万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6766771
• 关键词: artificial respiration; biological signal transduction; brain derived neurotrophic factor; cardiopulmonary resuscitation; cerebellum; cerebral cortex; cerebral ischemia /hypoxia; disease /disorder model; gene expression; heart arrest; hippocampus; hypothermia; laboratory rat; microarray technology; mitogen activated protein kinase; nerve injury; polymerase chain reaction; protein localization; protein structure function; reperfusion; transcription factor

DESCRIPTION (provided by applicant): Neurological injury after resuscitation from cardiac arrest is a major impediment to improving survival for victims who experience sudden cardiopulmonary collapse. Induction of hypothermia after restoration of circulation improves neurological recovery and is being advanced clinically. However, mild hypothermia does not completely reverse brain injury and a rational approach to improve this intervention is required. This project will employ a rat model of cardiac arrest that mimics the whole-brain injury, and that replicates the beneficial effects of post-resuscitation hypothermia. Preliminary studies indicate that hypothermia increases intracellular signaling in the brain via the extracellular signal regulated kinase, ERK (a mitogen activated protein kinase), and also increases brain tissue levels of brain-derived neurotrophic factor (BDNF). The time course of ERK and BDNF activation as well as the time window during which induction of hypothermia is beneficial suggest that induced hypothermia may affect new gene expression via these signaling systems. This proposal will expand our understanding of the beneficial effects of induced hypothermia and the by examining the relationship between BDNF, ERK and new gene expression in brain after cardiac arrest and resuscitation. This project will be divided into three specific aims: (1) The first aim will determine the role of neurotrophic factors in the control of ERK signaling after resuscitation and hypothermia. To accomplish this aim, we will employ neutralizing antibodies or antisense oligonucleotides or administration of exogenous neurotrophic factors after ischemia and hypothermic reperfusion. We will determine the localization and time-course of increased levels of particular neurotrophic factors in brain during hypothermic reperfusion. (2) The second aim will be to determine the participation of the downstream effectors of the ERK signaling pathway after resuscitation and hypothermia. We hypothesize that hypothermic reperfusion will increase activation of ERK-regulated transcription factors and expression of particular ERK-regulated gene products. Conversely, blockade of ERK activation is hypothesized to decrease expression of these same genes. (3) The final aim of the project will determine the participation of ERK and BDNF signaling in the hypothermia-induced improvement of neuronal survival and behavioral recovery after resuscitation. These pathways will be blocked and stimulated during hypothermic reperfusion, and behavioral and histological outcome for cardiac arrest will be measured.

描述（由申请人提供）： 心脏骤停复苏后的神经损伤是提高突发心肺衰竭患者生存率的主要障碍。 循环恢复后诱导低温可改善神经功能恢复，并正在临床上取得进展。然而，轻度低温并不能完全逆转脑损伤，需要采取合理的方法来改善这种干预措施。 该项目将采用心脏骤停的大鼠模型来模拟全脑损伤，并复制复苏后低温的有益效果。 初步研究表明，低温会通过细胞外信号调节激酶 ERK（一种丝裂原激活蛋白激酶）增加大脑中的细胞内信号传导，同时还会增加脑组织中脑源性神经营养因子 (BDNF) 的水平。 ERK 和 BDNF 激活的时间过程以及诱导低温有益的时间窗口表明诱导低温可能通过这些信号系统影响新基因的表达。 该提案将通过检查心脏骤停和复苏后大脑中 BDNF、ERK 和新基因表达之间的关系，扩大我们对诱导低温有益影响的理解。 该项目将分为三个具体目标： (1) 第一个目标是确定神经营养因子在复苏和低温后控制 ERK 信号传导中的作用。 为了实现这一目标，我们将在缺血和低温再灌注后使用中和抗体或反义寡核苷酸或施用外源神经营养因子。 我们将确定低温再灌注期间大脑中特定神经营养因子水平增加的定位和时间过程。 (2)第二个目标是确定复苏和低温后ERK信号通路下游效应器的参与。 我们假设低温再灌注将增加 E​​RK 调节转录因子的激活和特定 ERK 调节基因产物的表达。 相反，假设阻断 ERK 激活会降低这些相同基因的表达。 (3) 该项目的最终目标将确定 ERK 和 BDNF 信号传导在低温诱导的神经元存活改善和复苏后行为恢复中的参与。 这些通路将在低温再灌注期间被阻断和刺激，并且将测量心脏骤停的行为和组织学结果。