Functional studies of epilepsy mutations in Drosophila and human iPSC-derived neu

果蝇和人类 iPSC 衍生神经元癫痫突变的功能研究

基本信息

  • 批准号:
    8690664
  • 负责人:
  • 金额:
    $ 53.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-02-15 至 2019-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Mutations in the SCN1A gene encoding Nav1.1 voltage-gated sodium channels result in a variety of human seizure disorders. These include Dravet Syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Both DS and GEFS+ are autosomal dominant disorders but relatively little is known about the cellular mechanisms underlying seizure generation. Here we propose to assess the functional consequences of disease causing mutations on neuronal activity using two complementary, genetic model systems: knock-in Drosophila with SCN1A mutations and iPSC-derived neurons from patients with the same mutations. Our preliminary data demonstrate that knock-in of a GEFS+ SCN1A mutation (K1270T) into the Drosophila sodium channel gene, para, causes a semi-dominant temperature-induced seizure phenotype. Electrophysiological studies of GABAergic interneurons in the brains of adult GEFS+ flies reveal a novel cellular mechanism underlying heat-induced seizure. Consistent with disease symptoms in humans, the seizure phenotype caused by knock-in of a DS mutation (S1231R) is more severe than GEFS+. The congruence of the genotype-to-phenotype map between flies and human in this genetic disease model paves the way for use of knock-in Drosophila to study the mechanisms underlying these complex human genetic disorders. The first two aims are focused on use of Drosophila sodium channel knock-in lines to further explore the underlying cellular mechanisms contributing to heat-induced seizures and as a low cost, high efficiency, platform for discovery of genetic modifiers and drugs that suppress the seizure phenotype. In specific Aim 3 we will employ our expertise in stem cell biology to conduct parallel studies of neuronal activity in iPSC-derived neurons from patients with the same GEFS+ mutations examined in knock-in flies. Identification of common cellular mechanisms in these two model systems has the potential to identify targets for development of novel therapies to reduce or eliminate seizures in humans with epilepsy.
描述(由申请人提供):编码Nav1.1电压门控钠通道的SCN1A基因突变导致多种人类癫痫发作疾病。这些包括Dravet综合征(DS)和遗传性癫痫伴热性发作+ (GEFS+)。DS和GEFS+都是常染色体显性疾病,但对癫痫发作的细胞机制知之甚少。在这里,我们建议使用两个互补的遗传模型系统来评估引起疾病的突变对神经元活动的功能后果:具有SCN1A突变的敲入果蝇和来自具有相同突变的患者的ipsc衍生神经元。我们的初步数据表明,敲入果蝇钠通道基因的GEFS+ SCN1A突变(K1270T)会导致半显性温度诱导的癫痫发作表型。对成年GEFS+果蝇大脑中gaba能中间神经元的电生理研究揭示了热诱发癫痫发作的一种新的细胞机制。与人类疾病症状一致,由DS突变(S1231R)敲入引起的癫痫发作表型比GEFS+更严重。在这种遗传疾病模型中,果蝇和人类之间基因型-表型图谱的一致性为使用敲入果蝇来研究这些复杂的人类遗传疾病的机制铺平了道路。前两个目标集中在使用果蝇钠通道敲入系来进一步探索热诱发癫痫发作的潜在细胞机制,并作为低成本,高效率的平台,发现基因修饰剂和抑制癫痫发作表型的药物。在特定的Aim 3中,我们将利用我们在干细胞生物学方面的专业知识,对在敲入果蝇中检测的具有相同GEFS+突变的患者的ipsc衍生神经元的神经元活性进行平行研究。在这两种模型系统中确定共同的细胞机制有可能确定开发新疗法的靶点,以减少或消除癫痫患者的癫痫发作。

项目成果

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DIANE K O'DOWD其他文献

DIANE K O'DOWD的其他文献

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{{ truncateString('DIANE K O'DOWD', 18)}}的其他基金

Functional studies of epilepsy mutations in Drosophila and human iPSC-derived neu
果蝇和人类 iPSC 衍生神经元癫痫突变的功能研究
  • 批准号:
    9208170
  • 财政年份:
    2014
  • 资助金额:
    $ 53.91万
  • 项目类别:
Functional studies of epilepsy mutations in Drosophila and human iPSC-derived neu
果蝇和人类 iPSC 衍生神经元癫痫突变的功能研究
  • 批准号:
    8990893
  • 财政年份:
    2014
  • 资助金额:
    $ 53.91万
  • 项目类别:
PILOT STUDY--NICOTINE ROLE IN REGULATION OF NACHR IN DROSOPHILA
试点研究--尼古丁对果蝇 NACHR 调节的作用
  • 批准号:
    6660949
  • 财政年份:
    2002
  • 资助金额:
    $ 53.91万
  • 项目类别:
Role of Nicotine in Regulation of naChRs in Drosophila
尼古丁在果蝇 naChR 调节中的作用
  • 批准号:
    6421777
  • 财政年份:
    2001
  • 资助金额:
    $ 53.91万
  • 项目类别:
PILOT STUDY--NICOTINE ROLE IN REGULATION OF NACHR IN DROSOPHILA
试点研究--尼古丁在果蝇 NACHR 调节中的作用
  • 批准号:
    6495109
  • 财政年份:
    2001
  • 资助金额:
    $ 53.91万
  • 项目类别:
Role of Nicotine in Regulation of naChRs in Drosophila
尼古丁在果蝇 naChR 调节中的作用
  • 批准号:
    6634396
  • 财政年份:
    2001
  • 资助金额:
    $ 53.91万
  • 项目类别:
Role of Nicotine in Regulation of naChRs in Drosophila
尼古丁在果蝇 naChR 调节中的作用
  • 批准号:
    6776893
  • 财政年份:
    2001
  • 资助金额:
    $ 53.91万
  • 项目类别:
Role of Nicotine in Regulation of naChRs in Drosophila
尼古丁在果蝇 naChR 调节中的作用
  • 批准号:
    6914142
  • 财政年份:
    2001
  • 资助金额:
    $ 53.91万
  • 项目类别:
Role of Nicotine in Regulation of naChRs in Drosophila
尼古丁在果蝇 naChR 调节中的作用
  • 批准号:
    6515952
  • 财政年份:
    2001
  • 资助金额:
    $ 53.91万
  • 项目类别:
PILOT STUDY--NICOTINE ROLE IN REGULATION OF NACHR IN DROSOPHILA
试点研究--尼古丁在果蝇 NACHR 调节中的作用
  • 批准号:
    6349045
  • 财政年份:
    2000
  • 资助金额:
    $ 53.91万
  • 项目类别:

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    2009
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