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
- 来源:
- 关键词:
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)

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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:1061004110610041
- 财政年份:2022
- 资助金额:$ 4.87万$ 4.87万
- 项目类别:
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