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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.

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。