The MAPK Cascade in Epilepsy

描述：（逐字引用申请人摘要）癫痫是一种常见的 神经紊乱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。 这项提议的目的是评估MAPK信号通路在细胞凋亡中的作用。 癫痫的级联反应 我们和其他人已经证明MAPK调节K+通道活性和突触连接。 可塑性此外，MAPK激活导致细胞内的长期变化。 海马通过调节基因转录。最近的研究 在癫痫动物模型中证实了MAPK激活，尽管 癫痫中MAPK的下游靶点尚不清楚。我们认为MAPK 级联反应在急性和慢性阶段的发生中起着关键作用， 通过调节K+通道活性和基因转录来调节癫痫。 K+通道活性的调节可以影响膜的兴奋性， 最近的研究表明，具有K+通道的人类和遗传小鼠模型 突变具有癫痫表型。MAPK对转录因子的调控 如CREB可能有助于癫痫中观察到的慢性变化（即， 海马硬化）。我们的初步结果显示海马MAPK 激活，增加MAPK磷酸化的树突状K+通道 Kv4.2亚基，以及CREB磷酸化在红藻氨酸模型中的增加。 癫痫为了进一步支持MAPK级联在癫痫中的作用，我们 初步研究表明，抑制MAPK级联阻断表达 海人酸盐引起的边缘运动癫痫 在这个提议中，我们希望测试以下假设：1）MAPK级联是 在海人酸盐诱导的癫痫持续状态后在海马中激活， 对于红藻氨酸诱导的癫痫发生是必需的; 2）K+通道亚基， Kv4.2是癫痫的红藻氨酸盐模型中MAPK的效应子;和3）Kv4.2是癫痫的红藻氨酸盐模型中MAPK的效应子。 转录因子CREB是MAPK在红藻氨酸模型中的效应子。 癫痫 通过进一步明确MAPK信号级联在癫痫中的作用，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开发新的癫痫治疗方法。

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.