Project 3 - Development and investigation of murine models of channelopathy-associated epilepsy

项目 3 - 通道病相关癫痫小鼠模型的开发和研究

基本信息

  • 批准号:
    10247560
  • 负责人:
  • 金额:
    $ 54.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-30 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY – PROJECT 3 Epilepsy is a common neurological disorder that affects over 3 million Americans and has a substantial genetic contribution to its etiology. Mutation of voltage-gated ion channel genes (‘Channelopathies’), particularly voltage-gated sodium (NaV) and potassium (KV) channel genes, have emerged as a major cause of early onset epileptic encephalopathies. These severe epilepsy syndromes are often difficult to treat with existing therapies and are associated with adverse neurodevelopmental sequelae, making them a high priority for better treatment approaches like precision medicine. Functional characterization of a small number of epilepsy- associated voltage-gated ion channel mutations in heterologous expression systems have demonstrated a range of dysfunction, but it is presently difficult to extrapolate these results to in vivo effects. A major goal of our Center is to determine how well in vitro cellular models predict neuronal dysfunction and pharmacological responses in an intact brain. To accomplish this goal, Project 3 will focus on a series of representative mouse models with NaV and KV channel variants that cause prototypical patterns of dysfunction. We hypothesize that differences in the relative contribution of specific channels to excitability in various cell types within neuronal networks determine the net effect on excitation-inhibition balance and influence pharmacological response. Mouse models provide the opportunity to evaluate the effect of channel variants at the whole animal, cellular and network levels, as well as to investigate pharmacological responses. In Aim 1, we will develop mouse models to investigate NaV and KV channel variants associated with early onset epileptic encephalopathy. Mouse lines will be evaluated for neurological phenotypes and pharmacological response in vivo. In Aim 2, we will determine the impact of NaV and KV channel variants on channel properties and intrinsic cell excitability in acutely dissociated neurons isolated from mouse models, and then determine the effectiveness of pharmacological agents at normalizing channel activity and/or cell excitability in these neurons. These results will be compared with similar recordings from heterologous expression systems (Project 1) and patient-specific iPSC-derived neurons (Project 2) to establish important correlations between in vitro and in vivo models. In Aim 3, we will determine the impact of NaV and KV channel variants on intrinsic properties of neurons and consequent effects on network activity in brain slices, and then determine the effectiveness of pharmacological agents at normalizing aberrant cellular and network excitability. Results from Project 3 will provide mechanistic insight into the effects of channel dysfunction in intact brains, and determine therapeutic strategies that normalize excitation-inhibition balance and prevent/reduce seizures. Synergy between this project and Projects 1 and 2 include cross-platform comparisons of the same channelopathy-associated epilepsy variants, which will facilitate translation of results into valuable information for implementation of precision medicine in this common neurological disorder.
项目概要-项目3 癫痫是一种常见的神经系统疾病,影响超过300万美国人, 贡献于其病因。电压门控离子通道基因的突变(“脊髓病”),特别是 电压门控钠(NaV)和钾(KV)通道基因,已成为早发性的主要原因 癫痫性脑病这些严重的癫痫综合征通常难以用现有疗法治疗 并且与不良的神经发育后遗症有关,使其成为更好的优先事项。 像精准医疗这样的治疗方法。少数癫痫的功能表征- 在异源表达系统中相关的电压门控离子通道突变已经证明, 一系列的功能障碍,但目前很难将这些结果外推到体内效应。的一个主要目标 我们的中心是确定体外细胞模型预测神经元功能障碍和药理学的效果如何。 在一个完整的大脑中的反应。为了实现这一目标,项目3将集中在一系列具有代表性的鼠标 具有NaV和KV通道变体的模型,导致功能障碍的原型模式。我们假设 神经元内不同细胞类型中特定通道对兴奋性的相对贡献的差异 网络决定对兴奋-抑制平衡的净效应并影响药理反应。 小鼠模型提供了评估通道变体在整个动物、细胞和组织中的作用的机会。 和网络水平,以及研究药理学反应。在目标1中,我们将开发鼠标 模型研究与早发性癫痫性脑病相关的NaV和KV通道变体。 将评价小鼠品系的神经学表型和体内药理学反应。在目标2中, 将确定NaV和KV通道变体对通道特性和内在细胞兴奋性的影响, 从小鼠模型中分离急性分离的神经元,然后确定 药理学试剂使这些神经元中的通道活性和/或细胞兴奋性正常化。这些结果 将与来自异源表达系统(项目1)和患者特异性表达系统的类似记录进行比较。 iPSC衍生的神经元(项目2)建立体外和体内模型之间的重要相关性。在 目的3,我们将确定NaV和KV通道变体对神经元内在特性的影响, 随后对脑切片中网络活动的影响,然后确定药理学的有效性。 使异常的细胞和网络兴奋性正常化的药物。项目3的结果将提供 深入了解通道功能障碍在完整大脑中的影响,并确定治疗策略, 使兴奋-抑制平衡正常化并预防/减少癫痫发作。本项目与项目之间的协同作用 1和2包括相同通道病变相关癫痫变异的跨平台比较, 将有助于将结果转化为有价值的信息,以实施精准医学, 常见的神经系统疾病

项目成果

期刊论文数量(0)
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专利数量(0)

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Jennifer A Kearney其他文献

Jennifer A Kearney的其他文献

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{{ truncateString('Jennifer A Kearney', 18)}}的其他基金

Genetic Mapping of Modifier Loci in a Mouse Model KCNB1 Encephalopathy
KCNB1 脑病小鼠模型修饰位点的遗传图谱
  • 批准号:
    10753301
  • 财政年份:
    2023
  • 资助金额:
    $ 54.99万
  • 项目类别:
Development of a novel anti-neuroinflammatory experimental therapeutic for epilepsy and Alzheimer's risk
开发一种针对癫痫和阿尔茨海默病风险的新型抗神经炎症实验疗法
  • 批准号:
    10255597
  • 财政年份:
    2021
  • 资助金额:
    $ 54.99万
  • 项目类别:
Project 3 - Development and investigation of murine models of channelopathy-associated epilepsy
项目 3 - 通道病相关癫痫小鼠模型的开发和研究
  • 批准号:
    10477456
  • 财政年份:
    2018
  • 资助金额:
    $ 54.99万
  • 项目类别:
Genetic Modifiers of Childhood Epilepsy
儿童癫痫的基因修饰
  • 批准号:
    10328565
  • 财政年份:
    2014
  • 资助金额:
    $ 54.99万
  • 项目类别:
Genetic Modifiers of Childhood Epilepsy
儿童癫痫的基因修饰
  • 批准号:
    9980137
  • 财政年份:
    2014
  • 资助金额:
    $ 54.99万
  • 项目类别:
Combined Approach to Genetic Modifiers of Inherited Epilepsy
遗传性癫痫基因修饰的综合方法
  • 批准号:
    9021876
  • 财政年份:
    2014
  • 资助金额:
    $ 54.99万
  • 项目类别:
Genetic Modifiers of Childhood Epilepsy
儿童癫痫的基因修饰
  • 批准号:
    10132402
  • 财政年份:
    2014
  • 资助金额:
    $ 54.99万
  • 项目类别:
Genetic Modifiers of Childhood Epilepsy
儿童癫痫的基因修饰
  • 批准号:
    10539313
  • 财政年份:
    2014
  • 资助金额:
    $ 54.99万
  • 项目类别:
Genetic Modifiers of Childhood Epilepsy
儿童癫痫的基因修饰
  • 批准号:
    8759567
  • 财政年份:
    2014
  • 资助金额:
    $ 54.99万
  • 项目类别:
Genetic Modifiers of Childhood Epilepsy
儿童癫痫的基因修饰
  • 批准号:
    8914054
  • 财政年份:
    2014
  • 资助金额:
    $ 54.99万
  • 项目类别:

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