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

基本信息

  • 批准号:
    8259793
  • 负责人:
  • 金额:
    $ 16.32万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-06-01 至 2013-04-30
  • 项目状态:
    已结题

项目摘要

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 (EEC), 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 (Nay 1.1) channels. These mutations are found in Scnla, the gene encoding av 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. RELEVANCE (Seeinstructions): 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 help in the design of future pharmacological- or non-pharmacological therapies for SMEI and other epilepsy syndrome refractory to current antiepileptic drugs.
我是一名年轻的神经学家,毕业于田纳西大学,博士后 来自华盛顿大学的培训。我已经掌握了神经科学原理方面的扎实知识 以及以分离细胞和脑片电生理学为核心的优秀技术专长。我的长期任期 职业目标是建立一个研究实验室,作为一名独立的调查员,专注于理解和 开发神经疾病的治疗方法。此外,我希望教授和培训卫生专业人员和 科学家们。为了实现这些目标,我打算将这笔赠款的3-5年奖励期专门用于 扩大我的科学知识,提高研究技能。这项提议的科学活动将 包括参加研讨会、期刊俱乐部、国家和国际会议;编写手稿 用于出版;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,包括用脑电图仪记录活体动物的大脑活动 (EEC),培养细胞和表达离子通道,并进行基因突变。我将使用这些技巧 生酮饮食治疗婴儿期重症肌阵挛癫痫的疗效观察 (SMEI,也就是众所周知的Drave综合症)在华盛顿大学使用了这种疾病的小鼠模型, 全国领先的研究机构之一。 SMEI是一种非常恶性的儿童癫痫,最近被认为与突变有关 导致1型钠(NaY 1.1)通道减少。这些突变是在scnla中发现的,scnla是编码 AV1.1频道,它们阻止频道表达或降低功能。建立了SMEI的小鼠模型 在我们的实验室里,通过引入阻止scnla基因表达的突变。这些突变小鼠已经减少了 NAV 1.1钠电流,复制人SMEI的主要临床特征,包括严重癫痫发作 和共济失调。大多数抗癫痫药物都不能很好地控制人类SMEI发作。生酮饮食是一种 卡路里限制方案,提供脂肪、碳水化合物和蛋白质的比例约为4:1。这 节食疗法在控制难以控制的癫痫发作方面往往更有效,比如在SMEI中。然而, 其抗癫痫疗效的机制尚不清楚。提出的研究具有 目的:1)确定生酮饮食对小鼠的抗惊厥和抗癫痫作用。 2)评估神经功能和钠通道表达的变化。 生酮饮食的疗效;3)探讨生酮饮食对脑功能的影响 电压门控钠通道。 相关性(请参阅说明): 这些研究将通过揭示生酮饮食的作用机制来促进对其作用机制的理解。 对NAV通道表达和功能的影响以及对神经元兴奋性和癫痫发作的影响 敏感度。此外,本研究将提供新的见解,可能有助于未来的设计 SMEI和其他难治性癫痫综合征的药物或非药物治疗 目前的抗癫痫药物。

项目成果

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Franck K Kalume其他文献

Franck K Kalume的其他文献

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{{ truncateString('Franck K Kalume', 18)}}的其他基金

Cell type selective viral tools to interrogate and correct non-human primate and human brain circuitry
用于询问和纠正非人类灵长类动物和人类大脑回路的细胞类型选择性病毒工具
  • 批准号:
    10462660
  • 财政年份:
    2020
  • 资助金额:
    $ 16.32万
  • 项目类别:
Cell type selective viral tools to interrogate and correct non-human primate and human brain circuitry
用于询问和纠正非人类灵长类动物和人类大脑回路的细胞类型选择性病毒工具
  • 批准号:
    10249365
  • 财政年份:
    2020
  • 资助金额:
    $ 16.32万
  • 项目类别:
Cell type selective viral tools to interrogate and correct non-human primate and human brain circuitry
用于询问和纠正非人类灵长类动物和人类大脑回路的细胞类型选择性病毒工具
  • 批准号:
    10025520
  • 财政年份:
    2020
  • 资助金额:
    $ 16.32万
  • 项目类别:
Mechanisms of epilepsy-related death in Leigh syndrome
Leigh 综合征癫痫相关死亡的机制
  • 批准号:
    10186834
  • 财政年份:
    2017
  • 资助金额:
    $ 16.32万
  • 项目类别:
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:
    8059678
  • 财政年份:
    2009
  • 资助金额:
    $ 16.32万
  • 项目类别:
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
  • 财政年份:
    2009
  • 资助金额:
    $ 16.32万
  • 项目类别:
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:
    8641086
  • 财政年份:
    2009
  • 资助金额:
    $ 16.32万
  • 项目类别:
Therapeutic effects of ketogenic diet in mouse model of severe myoclonic epilepsy
生酮饮食对严重肌阵挛癫痫小鼠模型的治疗作用
  • 批准号:
    7660566
  • 财政年份:
    2009
  • 资助金额:
    $ 16.32万
  • 项目类别:

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