The MAPK Cascade in Epilepsy

描述：(逐字摘自申请者的摘要)癫痫是一种常见的 神经性疾病。癫痫领域的基础研究主要集中在 了解这种疾病背后的细胞和分子机制。 该提案的目标是评估MAPK信号转导的作用 卡戴克在癫痫中发挥作用。 我们和其他人已经证明，MAPK调节K+通道活性和突触 可塑性。此外，MAPK的激活导致了长时间的改变 通过基因转录调控海马体。最近的研究表明 在癫痫动物模型中显示了MAPK的激活，尽管 癫痫中MAPK的下游靶点尚不清楚。我们建议MAPK 级联在急性期和慢性期的发生中起着关键作用 通过K+通道活性和基因转录调节癫痫。 K+通道活性的调节可以影响膜的兴奋性，并且 最近的研究表明，人类和遗传小鼠模型具有K+通道 突变具有癫痫的表型。MAPK对转录因子的调控 例如CREB可能有助于癫痫的慢性改变(即 海马区硬化)。我们的初步结果显示，海马区MAPK 激活，增加树突状K+通道MAPK的磷酸化 Kv4.2亚基，并增加红藻氨酸模型中CREB的磷酸化 癫痫。为了进一步支持MAPK级联反应在癫痫中的作用，我们有 初步研究表明，抑制MAPK级联反应可阻断该基因的表达 红藻氨酸诱导的边缘运动性癫痫。 在这个提议中，我们希望检验以下假设：1)MAPK级联是 海人酸致癫痫持续状态后海马区的激活 红藻氨酸致痫所必需的；2)K+通道亚单位， Kv4.2，在海人癫痫模型中是MAPK的效应器； 转录因子CREB是KAIN模型中MAPK的效应因子 癫痫。 通过进一步确定MAPK信号通路在癫痫中的作用，我们希望 以深入了解导致这种疾病的基本机制。因此， 这些研究可能会导致癫痫新疗法的开发。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Epilepsy is a common neurological disorder. Basic research in the field of epilepsy has focused on understanding the cellular and molecular mechanisms that underlie the disorder. The goal of this proposal is to evaluate the role that the MAPK signaling cascade plays in epilepsy. We and others have shown that MAPK regulates K+ channel activity and synaptic plasticity. Furthermore MAPK activation leads to long-lasting changes in the hippocampus through regulation of gene transcription. Recent studies have demonstrated MAPK activation in animal models of epilepsy, although the downstream targets of MAPK in epilepsy are unknown. We propose that the MAPK cascade plays a critical role in the genesis of the acute and chronic phases of epilepsy through regulation of K+ channel activity and gene transcription. Regulation of K+ channel activity could impact membrane excitability, and recent studies have shown that humans and genetic mouse models with K+ channel mutations have an epilepsy phenotype. MAPK regulation of transcription factors such as CREB could contribute to the chronic changes seen in epilepsy (i.e. hippocampal sclerosis). Our preliminary results show hippocampal MAPK activation, an increase in MAPK phosphorylation of a dendritic K+ channel subunit, Kv4.2, and increases in CREB phosphorylation in the kainate model of epilepsy. To further support a role for the MAPK cascade in epilepsy we have pilot studies showing that inhibition of the MAPK cascade blocks the expression of kainate-induced limbic motor seizures. In this proposal we wish to test the hypotheses that: 1) the MAPK cascade is activated in hippocampus following kainate-induced status epilepticus and is necessary for kainate-induced epileptogenesis; 2) the K+ channel subunit, Kv4.2, is an effector of MAPK in the kainate model of epilepsy; and 3) the transcription factor, CREB, is an effector of MAPK in the kainate model of epilepsy. By further defining the role of the MAPK signaling cascade in epilepsy we hope to gain insight into the basic mechanisms contributing to this disorder. Thus these studies may lead to the development of new treatments for epilepsy.