Gluconeogenic control of Dravet Syndrome

Dravet 综合征的糖异生控制

基本信息

批准号：
10415061
负责人：
Scott C Baraban
金额：
$ 46.32万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10415061
关键词：
Address Adrenergic Agents Age Animal Model Anxiety Behavior Behavioral Bioenergetics Biopsy Branched-Chain Amino Acids Cell Respiration Childhood Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cytosol Data Defect Developmental Delay Disorders Down-Regulation Embryo Energy Metabolism Enzymes Epilepsy Fishes Gene Expression Genes Genetic Gluconeogenesis Glucose Glycerol Glycolysis Guanosine Triphosphate Human Hypoglycemia Impairment Investigation Laboratories Larva Life Link Mediating Metabolic Metabolism Methodology Mitochondria Modeling Mus Muscle Outcome Oxaloacetates Oxygen Consumption Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenocopy Phenotype Play Pyruvate Reporting Research Rest Risk Role Seizures Serotonin Sleep disturbances Sodium Channel Source Starvation Steroids Testing Therapeutic Therapeutic Intervention Time Up-Regulation Zebrafish acquired epilepsy base behavioral impairment blood glucose regulation childhood epilepsy comorbidity de novo mutation disease phenotype dravet syndrome drug discovery glucose metabolism inhibitor innovation insight ketogenic diet knock-down mutant novel sudden unexpected death in epilepsy virtual voltage

项目摘要

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.

尽管代谢改变正在迅速成为癫痫的一个关键特征，但尚未得到证实。对任何遗传形式的小儿癫痫进行系统研究。 Dravet 综合征 (DS) 与电压激活钠的从头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患者患有顽固性疾病生命早期癫痫发作和使人衰弱的合并症。相关合并症中的能量代谢 DS 几乎尚未被探索。为了解决这一未满足的需求，最近的合作研究我们的两个实验室显示，经过验证的糖酵解和耗氧率有所下降 DS 的斑马鱼模型，即 scn1Lab 突变体。这伴随着关键的下调糖异生途径中的酶 pck1 和 pck2。在这里，我们假设能量 DS 中由于葡萄糖失调而发生紊乱，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 将确定药理学是否抑制 pck1 和/或 pck2 会导致野生型斑马鱼的代谢和行为缺陷。目标 2 将确定 pck1 和/或 pck2 的药理学操作是否具有治疗作用 scn1Lab 突变斑马鱼。这些研究有望提供一个机制解释 DS 中观察到的代谢缺陷可能为治疗干预提供新的途径。