Project 2 - Investigation of human neuron models of channelopathy-associated epilepsy

项目 2 - 通道病相关癫痫的人类神经元模型的研究

基本信息

  • 批准号:
    10247557
  • 负责人:
  • 金额:
    $ 36.84万
  • 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

In Project 2 we will determine the functional consequences of epilepsy-associated ion channel gene variants using human neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs). We will initially focus on the SCN2A and KCNQ2 genes, which encode the voltage-gated Na+ (NaV1.2) and K+ (KV7.2) channels respectively. Mutations in SCN2A and KCNQ2 are responsible for monogenic early onset epileptic encephalopathy (EE) with overlapping clinical features and diverse severity. Collectively, variants in these two genes account for ~10% of all mutations identified in genetic epilepsy. The molecular pathogenic mechanisms responsible for the clinical manifestations of KCNQ2- and SCN2A-related epilepsies remain largely unknown. More importantly, no targeted therapeutic approach capable of diminishing seizure burden and improving developmental outcomes exists for these devastating neurological disorders. In Aim 1, we will use patient- specific cortical neurons to elucidate the functional consequences of epilepsy-associated KCNQ2 and SCN2A variants. We will specifically examine cortical excitatory and inhibitory neurons derived from existing patient- specific iPSC lines with pathogenic variants and corresponding isogenic control lines. We will use a combination of transcriptional profiling (single-cell RNA-sequencing) with electrophysiological approaches (whole cell patch clamp recording and high-throughput optogenetic recordings) to determine the impact of mutations on neuronal function and excitability. In Aim 2, we will assess the intrinsic excitability of patient neurons before and after treatment with NaV channel blockers and KV7 agonists that have clinical efficacy in the patients from whom the cells were derived. Our goal will be to rank the in vitro effectiveness of drugs in restoring normal neuron excitability for each genetic variant, and then to correlate the in vitro drug responses with the clinical responses to AEDs documented for these patients. This project entails a strategic collaboration between Dr. Kiskinis, whose lab focuses on using stem cell-based approaches to establish models of neurological disease, and Q-State Biosciences, Inc., which under the scientific leadership of Dr. McManus has been developing optogenetic technologies to enable high-throughput electrical recordings of human neurons and drug screening platforms for epilepsy syndromes. This project will work closely with the other Center teams, including Core A (Variant Prioritization and Curation Core), Project 1 (High-Throughput Functional Evaluation of Ion Channel Variants) and Project 3 (Development and Investigation of Murine Models of Channelopathy-associated Epilepsy). Core A is building tools to prioritize variants for experimental evaluation by the three Center projects. Correlation of findings from Project 2 with those of Projects 1 and 3 will help determine the reliability and accuracy of iPSC technology to predict in vivo physiology and pharmacology. Our findings will impact the field by demonstrating mechanistic effects of channelopathy-associated epilepsy variants, and by providing a systematic evaluation of human neuron platforms for precise drug selection.
在项目2中,我们将确定癫痫相关离子通道基因变异的功能后果

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Evangelos Kiskinis其他文献

Evangelos Kiskinis的其他文献

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{{ truncateString('Evangelos Kiskinis', 18)}}的其他基金

Defining the Mechanisms by Which Mutations in DNAJC7 Increase Susceptibility to ALS/FTD
确定 DNAJC7 突变增加 ALS/FTD 易感性的机制
  • 批准号:
    10645510
  • 财政年份:
    2023
  • 资助金额:
    $ 36.84万
  • 项目类别:
Investigating the Contribution of ALS/FTD-Associated Mutations in the NEK1 Kinase to Disease Pathophysiology
研究 NEK1 激酶中 ALS/FTD 相关突变对疾病病理生理学的贡献
  • 批准号:
    10753020
  • 财政年份:
    2023
  • 资助金额:
    $ 36.84万
  • 项目类别:
Defining The Impaired Proteostasis Network in ALS Patient Motor Neurons
定义 ALS 患者运动神经元受损的蛋白质稳态网络
  • 批准号:
    9676717
  • 财政年份:
    2018
  • 资助金额:
    $ 36.84万
  • 项目类别:
Determining How Defective Nucleo-Cytoplasmic Trafficking Leads To Neurodegeneration In C9orf72-Related ALS And FTD
确定缺陷性核细胞质运输如何导致 C9orf72 相关 ALS 和 FTD 中的神经变性
  • 批准号:
    10112967
  • 财政年份:
    2018
  • 资助金额:
    $ 36.84万
  • 项目类别:
Determining How Defective Nucleo-Cytoplasmic Trafficking Leads To Neurodegeneration In C9orf72-Related ALS And FTD
确定缺陷性核细胞质运输如何导致 C9orf72 相关 ALS 和 FTD 中的神经变性
  • 批准号:
    10334500
  • 财政年份:
    2018
  • 资助金额:
    $ 36.84万
  • 项目类别:
Project 2 - Investigation of human neuron models of channelopathy-associated epilepsy
项目 2 - 通道病相关癫痫的人类神经元模型的研究
  • 批准号:
    10477453
  • 财政年份:
    2018
  • 资助金额:
    $ 36.84万
  • 项目类别:
Defining The Impaired Proteostasis Network in ALS Patient Motor Neurons
定义 ALS 患者运动神经元受损的蛋白质稳态网络
  • 批准号:
    9756483
  • 财政年份:
    2018
  • 资助金额:
    $ 36.84万
  • 项目类别:
Project 2 - Investigation of human neuron models of channelopathy-associated epilepsy
项目 2 - 通道病相关癫痫的人类神经元模型的研究
  • 批准号:
    9792297
  • 财政年份:
  • 资助金额:
    $ 36.84万
  • 项目类别:

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