The Circadian Molecular Clock is a Biomarker for Epilepsy in Focal Cortical Dysplasia

昼夜节律分子钟是局灶性皮质发育不良中癫痫的生物标志物

• 批准号: 10351603
• 负责人: Judy Shih-Hwa Liu
• 金额: $ 7.72万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351603
• 关键词: Administrative Supplement; Bioinformatics; Biological Markers; Brain region; Chronic; Cortical Dysplasia; Development; Epilepsy; Excision; Excitatory Synapse; Hippocampus (Brain); Histological Techniques; Human; Inhibitory Synapse; Knockout Mice; Laboratories; Learning; Maintenance; Mediating; Microscopy; Molecular Analysis; Mus; Neurologic; Neurons; Neurotransmitters; Partial Epilepsies; Presynaptic Terminals; Proteins; Publishing; RNA analysis; Regulation; Reporting; Role; Seizures; Stains; Synapses; System; Techniques; Testing; Therapeutic; Tissues; Training; bZIP Protein; base; brain tissue; circadian; excitatory neuron; experience; hippocampal pyramidal neuron; inhibitory neuron; molecular clock; mutant; nano-string; synaptogenesis; transcription factor; transcriptome; transcriptome sequencing

Abstract Focal epilepsy is the most common cause of epilepsy. The abnormal epileptogenic region of the brain that generates seizures or "seizure focus" is critically important because its removal often results in a complete cure of the epilepsy. However, this tissue is under studied. Our first transcriptome study demonstrated diminished expression of the CLOCK transcription factor in seizure focus in contrast to control tissue. In addition, the downstream targets of CLOCK, the PAR bZip transcriptions factors are also diminished in the seizure focus. The deletion of Par bZip transcription factors in mice causes epilepsy. Thus, the role of CLOCK in the seizure focus may be through its regulation of the Par bZip transcription factors. In our study of CLOCK, we find that the deletion of CLOCK changes synaptic numbers, especially in inhibitory synapses. However, the function of PAR bZip factors per se in synaptogenesis and synaptic maintenance has not been explored, despite reports of their roles in regulating neurotransmitter levels. Based on our published finding that increased neuronal hyperexcitability of CLOCK-deficient mutants is associated with changes in the number of inhibitory synaptic terminals on excitatory pyramidal neurons, we hypothesize that these changes are mediated by PAR bZip. The Aims of this Supplement will test the hypothesis that, as downstream effectors of CLOCK, PAR bZip transcription factors govern synaptic maintenance and stability (Aim 1), as well as the expression levels of synaptic proteins (Aim 2). Both Aims will utilize the triple PAR bZip knockout mouse, so that Sean will gain experience in histological techniques and advanced microscopy, as well as molecular analyses and bioinformatics.

抽象的 局灶性癫痫是癫痫的最常见原因。异常的癫痫病 产生癫痫发作或“癫痫发作焦点”的大脑区域至关重要，因为它 去除通常会导致癫痫的完全治愈。但是，该组织正在研究中。 我们的第一个转录组研究表明，时钟转录的表达降低 与控制组织相比，癫痫发作的因素。另外，下游目标 时钟，在癫痫发作的重点中，PAR BZIP转录因子也会减少。这 小鼠中PAR BZIP转录因子的缺失会导致癫痫。因此，时钟在 癫痫发作的重点可能是通过对PAR BZIP转录因子的调节。 在我们对时钟的研究中，我们发现时钟的删除会更改突触数， 特别是在抑制突触中。但是，PAR BZIP因子本身的功能 尽管有报道称突触生成和突触维护 在调节神经递质水平。根据我们发表的发现，神经元增加了 时钟缺陷突变体的过度兴奋与数量的变化有关 抑制性突触终末在兴奋性锥体神经元上，我们假设这些 变化是由PAR BZIP介导的。该补充的目的将检验以下假设： 作为时钟的下游效应子，PAR BZIP转录因子控制突触 维持和稳定性（AIM 1）以及突触蛋白的表达水平（AIM 2）。 这两个目标都将利用三重PAR BZIP敲除鼠标，以便Sean会获得经验 组织学技术和晚期显微镜以及分子分析和 生物信息学。