Hypothermia and Gene Expression After Cardiac Arrest

描述（由申请人提供）： 心脏骤停复苏后的神经损伤是提高心肺骤停患者生存率的主要障碍。 在循环恢复后诱导低温可改善神经恢复，并在临床上取得进展。然而，轻度低温并不能完全逆转脑损伤，需要一种合理的方法来改善这种干预。 这个项目将采用一种模拟全脑损伤的心脏骤停大鼠模型，并复制复苏后低温的有益效果。 初步研究表明，低温通过细胞外信号调节激酶ERK（一种促分裂原活化蛋白激酶）增加脑中的细胞内信号传导，并且还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表明诱导低温可能通过这些信号系统影响新的基因表达。 本研究将通过探讨脑源性神经营养因子（BDNF）、细胞外信号调节激酶（ERK）与心脏骤停复苏后脑内新基因表达的关系，扩大我们对诱导性低温的有益作用的认识。 该项目将分为三个具体目标： (1)第一个目标是确定复苏和低温后神经营养因子在ERK信号转导控制中的作用。 为了达到这一目的，我们将采用中和抗体或反义寡核苷酸或在缺血和低温再灌注后给予外源性神经营养因子。 我们将确定在低温再灌注过程中脑内特定神经营养因子水平升高的位置和时间过程。(2)第二个目的是确定复苏和低温后ERK信号通路下游效应子的参与。 我们假设低温再灌注将增加ERK调节的转录因子的激活和特定ERK调节的基因产物的表达。 相反，假设阻断ERK激活会降低这些相同基因的表达。 (3)该项目的最终目的是确定ERK和BDNF信号转导在脑下垂体诱导的复苏后神经元存活和行为恢复的改善中的参与。 这些通路将在低温再灌注期间被阻断和刺激，并将测量心脏骤停的行为和组织学结果。

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.