Hypothermia and Gene Expression After Cardiac Arrest

描述（由申请人提供）：

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.