Gluconeogenic control of Dravet Syndrome

虽然新陈代谢改变正在迅速成为癫痫的一个关键特征，但它并没有 对任何遗传形式的儿童癫痫进行了系统研究。德雷维综合征(DS)，a 与电压激活钠基因从头突变相关的灾难性儿童癫痫 Nav1.1是最常见的遗传性癫痫之一。DS患者患有难治性疾病 早期癫痫发作，以及衰弱的合并症。与合并症相关的能量代谢 患有DS的人实际上仍未被探索。为了解决这一未得到满足的需求，最近的合作研究 在我们的两个实验室中显示了糖酵解和氧耗率的降低 斑马鱼DS模型，即scn1Lab突变体。伴随而来的是对KEY的下调 糖异生途径中的酶，即pck 1和pck 2。在这里，我们假设能量 DS的中断是由于葡萄糖调节失调导致癫痫发作和/或合并疾病。 为了检验这一假设，我们提出了以下目标。目标1将确定药理作用是否 野生型斑马鱼中抑制pck 1和/或pck 2表型表型的代谢和行为缺陷。 目标2将确定对pck 1和/或pck 2的药理操作是否具有治疗作用 Scn1Lab突变体斑马鱼。这些研究承诺提供一种机制上的解释 在DS中观察到代谢缺陷，并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.