Epilepsy Mechanisms and the Path to Intervention

癫痫机制和干预途径

基本信息

  • 批准号:
    10704607
  • 负责人:
  • 金额:
    $ 4.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-15 至 2024-09-14
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Mutations in the SLC13A5 gene, which encodes a plasma membrane citrate transporter, result in a newly diagnosed form of genetic epilepsy termed early infantile epileptic encephalopathy, which is characterized by multi-focal seizures in neonates. These infants subsequently develop cognitive and behavioral deficits. Human genetics has identified both commonly occurring missense and deletion mutations, but it is not known how distinct genetic mutations affect disease presentation and seizure severity. We are addressing this question by characterizing an array of SLC13A5 mutant mouse models carrying: i) ablation of its endogenous murine Slc13a5 gene (knockout), ii) the most common patient mutation, the G222R point mutation (equivalent to the human mutation G219R), and iii) the second most common patient mutation, the T230M (equivalent to the human mutation T227M). Our preliminary data demonstrates that homozygous Slc13a5 knockout mouse demonstrates abnormal epileptiform electroencephalogram (EEG) profiles, while the G222R has seizures and significantly more severe epileptiform activity. Preliminary histopathology reveals differential interneuron reduction between the knockout and G222R, with the G222R additionally showing oligodendroglial loss. These results are consistent with our interpretation that specific missense mutations may acquire dominant gain-of-function effects which exacerbate vulnerability and neuronal hyperexcitability. The knockout has shown reduced excitatory and inhibitory postsynaptic activity suggestive of reduced neurotransmitter levels. We will further characterize these mutant mouse models with the following experiments: experiment 1.1, the characterization of interictal discharges and seizures in the mutant alleles using EEG, in parallel with analysis of brain histopathology. In experiment 1.2, I will apply electrophysiological techniques to investigate whether a deficiency in intracellular citrate transport in Slc13a5 knockout and missense mutations affects neuronal function by altering glutamate and GABA concentrations. A metabolomics screen for neurotransmitters will be performed to corroborate functional data. In experiment 1.3, I will investigate the effect of these SLC13A5 mutant proteins on cellular pathologies. Combined, these experiments will investigate the molecular and cellular mechanisms that contribute to the seizure phenotype in the SLC13A5 disease, which in turn will inform therapeutic approaches. I will acquire training in electrophysiology and molecular biology to follow through with these experiments. Our research training plan and ongoing professional development will provide me with skills to transition me to the next stages of my scientific career. In the postdoctoral stage, I plan to gain experience with gene therapy strategies in experimental models of nervous system disease. I will continue to investigate cellular and molecular mechanisms underlying brain disease, and to apply these findings to optimize gene therapy approaches. Furthermore, I will continue to develop the professional skills required to become an independent primary investigator at an academic research institution.

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)

暂无数据

数据更新时间:2024-06-01

Kelvin A DeLeon的其他基金

Epilepsy Mechanisms and the Path to Intervention
癫痫机制和干预途径
  • 批准号:
    10610041
    10610041
  • 财政年份:
    2022
  • 资助金额:
    $ 4.87万
    $ 4.87万
  • 项目类别:

相似国自然基金

时空序列驱动的神经形态视觉目标识别算法研究
  • 批准号:
    61906126
  • 批准年份:
    2019
  • 资助金额:
    24.0 万元
  • 项目类别:
    青年科学基金项目
本体驱动的地址数据空间语义建模与地址匹配方法
  • 批准号:
    41901325
  • 批准年份:
    2019
  • 资助金额:
    22.0 万元
  • 项目类别:
    青年科学基金项目
大容量固态硬盘地址映射表优化设计与访存优化研究
  • 批准号:
    61802133
  • 批准年份:
    2018
  • 资助金额:
    23.0 万元
  • 项目类别:
    青年科学基金项目
IP地址驱动的多径路由及流量传输控制研究
  • 批准号:
    61872252
  • 批准年份:
    2018
  • 资助金额:
    64.0 万元
  • 项目类别:
    面上项目
针对内存攻击对象的内存安全防御技术研究
  • 批准号:
    61802432
  • 批准年份:
    2018
  • 资助金额:
    25.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

In vivo feasibility of a smart needle ablation treatment for liver cancer
智能针消融治疗肝癌的体内可行性
  • 批准号:
    10699190
    10699190
  • 财政年份:
    2023
  • 资助金额:
    $ 4.87万
    $ 4.87万
  • 项目类别:
Deciphering Mechanisms of Astrocyte-BBB Interaction in Normal and Ischemic Stroke
解读正常和缺血性中风中星形胶质细胞-BBB相互作用的机制
  • 批准号:
    10585849
    10585849
  • 财政年份:
    2023
  • 资助金额:
    $ 4.87万
    $ 4.87万
  • 项目类别:
Genetic Dissection of Stress Responses in Shwachman-Diamond Syndrome
什瓦赫曼-戴蒙德综合征应激反应的基因剖析
  • 批准号:
    10594366
    10594366
  • 财政年份:
    2023
  • 资助金额:
    $ 4.87万
    $ 4.87万
  • 项目类别:
LRP1 as a novel regulator of CXCR4 in adult neural stem cells and post-stroke response
LRP1 作为成体神经干细胞和中风后反应中 CXCR4 的新型调节剂
  • 批准号:
    10701231
    10701231
  • 财政年份:
    2023
  • 资助金额:
    $ 4.87万
    $ 4.87万
  • 项目类别:
Elucidating signaling networks in Anterior Segment development, repair and diseases
阐明眼前节发育、修复和疾病中的信号网络
  • 批准号:
    10718122
    10718122
  • 财政年份:
    2023
  • 资助金额:
    $ 4.87万
    $ 4.87万
  • 项目类别: