Metabolic and Epigenetic Regulation of Genes Controlling Neuronal Plasticity

描述(申请人提供)：癫痫困扰着世界上约百分之一的人口。不幸的是，大约三分之一的受影响个人的癫痫发作不是由现有药物控制的。因此，迫切需要新的治疗方案，需要更好地了解调节神经系统可塑性的机制。我的实验室最近的工作表明，能量代谢的扰动可能代表了一种控制神经元可塑性的新途径(Garriga-Canut等人，2006年)。这项应用将探索代谢扰动控制神经元可塑性的各个方面的机制-具体地说，i)活动依赖基因的表观遗传调节，以及ii)控制小鼠海马区长期增强(LTP)的信号级联的代谢调节。我们以前发表的工作和最近的初步数据表明，能量代谢的两个关键感受器--AMP激活的蛋白激酶(AMPK)和C末端结合蛋白(CtBP)分别以急性细胞质和翻译后方式以及慢性表观遗传方式调节神经元的可塑性。AMPK和CtBP的功能都可以被体内耐受性良好的小分子药物调节，我们认为这两种药物都可能成为治疗癫痫的有吸引力的新治疗靶点。这一建议旨在解决能量代谢如何控制的广泛问题：i)基因转录的表观遗传调控；ii)神经元信号级联调控以调节海马区神经元的可塑性。这些发现将促进通过控制能量代谢传感器来控制癫痫等情况下的可塑性的治疗方法的产生。

DESCRIPTION (provided by applicant): Epilepsy afflicts around one percent of the world's population. Unfortunately approximately a third of all affected individuals do not have their seizures controlled by currently available drugs. Therefore there is a pressing need for new classes of therapeutic options, requiring an improved understanding of the mechanisms that regulate plasticity in the nervous system. Recent work from my lab suggests that perturbation of energy metabolism may represent a novel route to controlling neuronal plasticity (Garriga-Canut et al, 2006). This application will explore the mechanism by which metabolic perturbation controls aspects of neuronal plasticity - specifically, i) epigenetic regulation of activity- dependent genes and ii) metabolic regulation of signaling cascades that control Long Term Potentiation (LTP) in the mouse hippocampus. Our previously published work and more recent preliminary data suggests that two key sensors of energy metabolism -AMP activated Protein kinase (AMPK) and C-terminal Binding Protein (CtBP) act to regulate neuronal plasticity in an acute cytoplasmic and post-translational manner and also a chronic epigenetic manner respectively. The function of both AMPK and CtBP can be modulated with small molecule pharmaceuticals that are well tolerated in vivo and we propose that either might represent attractive novel therapeutic targets for the treatment of epilepsy. This proposal aims to address the broad question of how energy metabolism can control i) epigenetic regulation of gene transcription and ii) kinase regulation of neuronal signaling cascades to modulate neuronal plasticity in the hippocampus. The findings will facilitate the generation of therapies that work through controlling sensors of energy metabolism to control plasticity in conditions such as epilepsy.