Metabolic and Epigenetic Regulation of Genes Controlling Neuronal Plasticity

描述（由申请人提供）：癫痫困扰着世界上大约百分之一的人口。不幸的是，在所有受影响的人中，约有三分之一的人的癫痫发作没有得到现有药物的控制。因此，迫切需要新的治疗选择，需要对调节神经系统可塑性的机制有更好的理解。我的实验室最近的工作表明，能量代谢的扰动可能代表了控制神经元可塑性的新途径（Garriga-Canut et al, 2006）。本应用程序将探索代谢扰动控制神经元可塑性方面的机制-具体而言，i)活性依赖基因的表观遗传调控和ii)控制小鼠海马长期增强（LTP）的信号级联的代谢调控。我们之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传感器-AMP激活蛋白激酶（AMPK）和c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可塑性。AMPK和CtBP的功能都可以通过体内耐受良好的小分子药物来调节，我们认为这两种药物都可能成为治疗癫痫的新靶点。该提案旨在解决能量代谢如何控制i)基因转录的表观遗传调控和ii)神经元信号级联的激酶调控以调节海马神经元可塑性的广泛问题。这一发现将促进通过控制能量代谢传感器来控制癫痫等疾病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. PUBLIC HEALTH RELEVANCE: Epilepsy afflicts around one percent of the world's population but 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 molecules and mechanisms that function in the nervous system. Recent work from my lab suggests that metabolism may represent a novel route to controlling epilepsy and this application will explore the mechanism by which 2 sensors of metabolism (CtBP and AMPK) control neuronal function or 'plasticity'. The mechanisms and drugs we study here will hopefully lead to therapies that result in 'no seizures and no side effects' for the millions of people around the world with epilepsy.