Understanding the Etiology of CASK Associated Epileptic Encephalopathy

了解 CASK 相关癫痫性脑病的病因

基本信息

项目摘要

PROJECT ABSTRACT Epileptic encephalopathies (EEs) are severe brain disorders of early infantile and childhood age onset characterized by epileptic seizures, abnormal electroencephalogram (EEG), severe cognitive and behavioral impairments that might lead to early death. It is estimated that ~2.9 million Americans live with epilepsy and the mortality rate in people with epilepsy is ~2-3 times higher than the general population. Several genetic mutations associate with EEs including mutations in the X-linked intellectual disability gene CASK that are found in patients with Ohtahara syndrome (OS) and West Syndrome (WS). Constitutive CASK deletion in mammals is incompatible with life and the prognosis of CASK hemizygous male patients remains extremely grim. The precise function of CASK and the potential mechanisms by which CASK mutation produces EE remains obscure. Because the constitutive CASK-/- knockout mice exhibited neonatal lethality, we recently generated a novel mouse model of EE by deleting CASK specifically from the neurons (CASKNKO). We found that CASKNKO mice display severe growth retardation, recurrent tonic spasms, EEG anomalies, and myoclonus beginning postnatal day 17 that leads to death by postnatal day 25. Multiple studies have shown that CASK protein is localized at the mitochondrial membranes. Recently, CASK gene expression was found to be regulated in an NAD+/Sirtuin1 dependent manner in mouse neurons. Moreover, we found that mammalian CASK interacts and co-localizes with mitochondrial proteins, and significantly modulates mitochondrial function and number. Based on the evidences from literature and our findings we hypothesize that CASK plays a role in brain mitochondrial function and metabolism, and is critical for optimum neuronal excitability in vivo. To test this hypothesis, we will examine the brain mitochondrial, metabolic, and electrophysiological functional changes as well as synaptic excitatory/inhibitory balance in the CASKNKO mice. We will further identify the specific domain/s of CASK that interacts with mitochondrial proteins, and determine if SIRT1-dependent mitochondrial biogenesis pathway is dysregulated in the brain of CASKNKO mice. Experiments will be performed before and after the onset of myoclonus to distinguish between a potential cause and consequence relation with the disease. We will also test if pharmacological activation of NAD+/SIRT1 pathway can stimulate mitochondrial biogenesis in the brain and CASK expression in glial cells to rescue EE phenotype in the CASKNKO mice. Success in the proposed project will uncover how loss of neuronal CASK alters mitochondrial and synaptic functions to produce EE. The long-term goal of our project is to use the novel CASKNKO EE mouse model to identify potential disease biomarkers and test therapeutic strategies for clinical intervention.
项目摘要

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Sarika Srivastava其他文献

Sarika Srivastava的其他文献

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{{ truncateString('Sarika Srivastava', 18)}}的其他基金

Understanding the Etiology of CASK Associated Epileptic Encephalopathy
了解 CASK 相关癫痫性脑病的病因
  • 批准号:
    10533820
  • 财政年份:
    2021
  • 资助金额:
    $ 41.54万
  • 项目类别:
Understanding the Etiology of CASK Associated Epileptic Encephalopathy
了解 CASK 相关癫痫性脑病的病因
  • 批准号:
    10378009
  • 财政年份:
    2021
  • 资助金额:
    $ 41.54万
  • 项目类别:
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