Therapeutic effects of ketogenic diet in a mouse model of severe myoclinic epilep

生酮饮食对重症肌阵挛性癫痫小鼠模型的治疗作用

• 批准号: 7848142
• 负责人: Franck K Kalume
• 金额: $ 15.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848142
• 关键词: A Mouse; Animal Model; Animals; Antiepileptic Agents; Ataxia; Award; Brain; Caloric Restriction; Carbohydrates; Cell physiology; Cells; Childhood; Chronic; Clinical; Control Animal; Cultured Cells; Diet; Disease; Educational process of instructing; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Fatty acid glycerol esters; Financial compensation; Future; Gene Expression; Gene Mutation; Genes; Goals; Grant; Health Professional; Hippocampal Formation; Hippocampus (Brain); Human; Immunohistochemistry; In Situ Hybridization; Individual; Institution; International; Interneurons; Ion Channel; Journals; Ketone Bodies; Knowledge; Learning; Life; Malignant - descriptor; Manuscripts; Messenger RNA; Monitor; Mus; Mutant Strains Mice; Mutation; Myoclonic Epilepsies; Neurons; Neurosciences; Pharmaceutical Preparations; Postdoctoral Fellow; Predisposition; Property; Proteins; Publications; Regimen; Regulation; Research; Research Activity; Research Personnel; Scientist; Sclerosis; Seizures; Slice; Sodium; Sodium Channel; Solid; Students; Syndrome; Technical Expertise; Techniques; Tennessee; Therapeutic; Therapeutic Effect; Training; Universities; Video Recording; Washington; Work; brain cell; career; feeding; infancy; inhibitory neuron; insight; ketogenic diet; meetings; mouse model; mutant; nervous system disorder; novel; post-doctoral training; prevent; protective effect; protein expression; research study; skills; voltage

DESCRIPTION (provided by applicant): I am a young neuroscientist with a graduate training from the University of Tennessee and postdoctoral training from the University of Washington. I have acquired solid knowledge in the principles of neuroscience and excellent technical expertise centered on dissociated cell and brain slice electrophysiology. My long term career goals are to establish a research lab, as an independent investigator, focused on understanding and developing cures for neurological disorders. In addition, I expect to teach and train health professionals and scientists. To attain these goals, I intend to dedicate the 3-5 year award period of this grant toward expanding my scientific knowledge and enhancing research skills. The scientific activities of this proposal will include participating in seminars, journal clubs, national and international meetings; preparing manuscripts for publication; and training students and junior post-doctoral fellows. The research activities will include learning novel techniques for me including recording brain activity in live animals by electroencephalography (EEG), culturing cells and expressing ion channels, and making gene mutations. I will use these techniques to intensively investigate the therapeutic properties of ketogenic diet in severe myoclonic epilepsy in infancy (SMEI, as known as Dravet syndrome) using a mouse model of the disorder at the University of Washington, one of the leading research institutions in the nation. SMEI is a very malignant form of childhood epilepsy that has been associated recently with mutations causing reduced type 1 sodium (Nav 1.1) channels. These mutations are found in Scnla, the gene encoding Nav 1.1 channels; they prevent channel expression or reduce function. A mouse model of SMEI was created in our lab by introducing mutations that prevent Scnla gene expression. These mutant mice have reduced Nav 1.1 sodium current and reproduce the main clinical features of human SMEI including severe seizures and ataxia. Human SMEI seizures are not well-controlled with most anti epileptic drugs. Ketogenic diet is a calorie restricted regimen that provides a ratio of fat to carbohydrate and protein combined of about 4:1. This diet is often more efficacious in managing difficult-to-control seizures such as those in SMEI. However, the mechanisms responsible for its antiepileptic efficacy are not understood. The research proposed has the following specific aims: 1) To determine the anticonvulsive and antiepileptic effects of ketogenic diet in mouse SMEI; 2) to evaluate changes in neuronal function and sodium channel expression underlying the therapeutic effects of ketogenic diet; 3) to investigate the effects of ketogenic diet on the function of 'brain' voltage-gated sodium channels. These studies will advance the understanding of the mechanisms of action of ketogenic diet by revealing its impacts on Nav channel expression and function as well as on neuron excitability and seizure susceptibility. Furthermore, this study will give new insights that may suggest future pharmacological or non-pharmacological therapies for SMEI.

描述（由申请人提供）：我是一位年轻的神经科学家，拥有田纳西大学的研究生培训和华盛顿大学的博士后培训。我获得了扎实的神经科学原理知识和以分离细胞和脑切片电生理学为中心的出色技术专业知识。我的长期职业目标是作为一名独立研究者建立一个研究实验室，专注于了解和开发神经系统疾病的治疗方法。此外，我希望教授和培训卫生专业人员和科学家。为了实现这些目标，我打算将这笔资助的 3-5 年奖励期用于扩展我的科学知识和提高研究技能。该提案的科学活动将包括参加研讨会、期刊俱乐部、国内和国际会议；准备出版手稿；并培训学生和初级博士后研究员。研究活动将包括为我学习新技术，包括通过脑电图（EEG）记录活体动物的大脑活动、培养细胞和表达离子通道，以及进行基因突变。我将利用这些技术，在华盛顿大学（美国领先的研究机构之一）的小鼠模型上，深入研究生酮饮食对婴儿期严重肌阵挛癫痫（SMEI，又称 Dravet 综合征）的治疗特性。 SMEI 是儿童癫痫的一种非常恶性的形式，最近与导致 1 型钠 (Nav 1.1) 通道减少的突变有关。这些突变存在于 Scnla（编码 Nav 1.1 通道的基因）中；它们阻止通道表达或减少功能。我们的实验室通过引入阻止 Scnla 基因表达的突变创建了 SMEI 小鼠模型。这些突变小鼠的 Nav 1.1 钠电流降低，并再现了人类 SMEI 的主要临床特征，包括严重癫痫发作和共济失调。大多数抗癫痫药物不能很好地控制人类 SMEI 癫痫发作。生酮饮食是一种热量限制疗法，脂肪与碳水化合物和蛋白质的比例约为 4:1。这种饮食对于控制难以控制的癫痫发作（例如 SMEI 中的癫痫发作）通常更有效。然而，其抗癫痫功效的机制尚不清楚。提出的研究有以下具体目的：1）确定生酮饮食对小鼠 SMEI 的抗惊厥和抗癫痫作用； 2）评估生酮饮食治疗效果背后的神经元功能和钠通道表达的变化； 3）研究生酮饮食对“大脑”电压门控钠通道功能的影响。这些研究将通过揭示生酮饮食对 Nav 通道表达和功能以及神经元兴奋性和癫痫易感性的影响，促进对生酮饮食作用机制的理解。此外，这项研究将提供新的见解，可能为 SMEI 的未来药物或非药物疗法提供建议。