Gluconeogenic control of Dravet Syndrome

虽然代谢改变正在迅速成为癫痫的一个关键特征，但它还没有被广泛接受。 系统地研究了任何遗传形式的小儿癫痫。Dravet综合征（DS），a 与电压激活钠基因的新生突变相关的灾难性儿童癫痫 通道，Nav1.1是最常见的遗传性癫痫之一。DS患者患有难治性 早期癫痫和衰弱性合并症合并症相关的能量代谢 几乎还未被探索过为了解决这一未满足的需求，最近的合作研究 在我们的两个实验室中发现，在经过验证的 DS的斑马鱼模型，即，scn 1 Lab突变体。这伴随着下调的关键 酶，pck 1和pck 2，在胚胎发育途径中。在这里，我们假设能量 由于葡萄糖调节异常导致DS中断，导致癫痫发作和/或合并症。 提出以下目标来检验这一假设。目标1将确定是否药理学 抑制pck 1和/或pck 2表型在野生型斑马鱼中代谢和行为缺陷。 目的2将确定pck 1和/或pck 2的药理学操作是否在以下情况中具有治疗性： scn 1 Lab突变斑马鱼。这些研究有望对这些现象提供一种机制性的解释。 在DS中观察到代谢缺陷，可能为治疗干预提供新的途径。

Although altered metabolism is rapidly emerging as a key feature of epilepsies, it has not been systematically investigated in any genetic form of pediatric epilepsy. Dravet syndrome (DS), a catastrophic childhood epilepsy associated with de novo mutations in a voltage-activated sodium channel, Nav1.1 is one of the most common genetic epilepsies. DS patients suffer with intractable early-life seizures, and debilitating comorbidities. Energy metabolism in comorbidities associated with DS remain virtually unexplored. To address this unmet need, recent collaborative research in our two laboratories revealed decreased glycolytic and oxygen consumption rates in a validated zebrafish model of DS i.e., scn1Lab mutants. This was accompanied by downregulation of key enzymes, pck1 and pck2, in the gluconeogenesis pathway. Here, we hypothesize that energy disruption occurs in DS due to glucose dysregulation resulting in seizures and/or comorbidities. The following aims are proposed to test this hypothesis. Aim 1 will determine if pharmacological inhibition of pck1 and/or pck2 phenocopies metabolic and behavioral deficits in wildtype zebrafish. Aim 2 will determine if pharmacological manipulation of pck1 and/or pck2 is therapeutic in scn1Lab mutant zebrafish. These studies promise to provide a mechanistic explanation of the metabolic defects observed in DS and could suggest novel avenues for therapeutic intervention.