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

摘要 癫痫病的病因有哪些？异常癫痫 大脑中产生癫痫发作或“癫痫发作焦点”的区域至关重要，因为它 切除通常导致癫痫的完全治愈。然而，这种组织正在研究中。 我们的第一个转录组研究表明，CLOCK转录的表达减少， 与对照组织相比，此外，下游目标 CLOCK，PAR bZip转运因子在癫痫病灶中也减少。的 小鼠中Par bZip转录因子的缺失导致癫痫。因此，时钟在 癫痫灶可能是通过其对Par bZip转录因子的调节而形成的。 在我们对CLOCK的研究中，我们发现CLOCK的缺失改变了突触数量， 尤其是抑制性突触。然而，PAR bZip因子本身在 突触发生和突触维持尚未被探索，尽管有报道它们的作用 调节神经递质水平。根据我们发表的发现， CLOCK缺陷突变体的过度兴奋性与细胞内细胞数量的变化有关。 兴奋性锥体神经元上的抑制性突触末梢，我们假设这些 变化由PAR bZip介导。本补编的目的将检验以下假设： 作为CLOCK的下游效应子，PAR bZip转录因子调控突触的形成， 维持和稳定性（目标1），以及突触蛋白的表达水平（目标2）。 这两个目标将利用三重PAR bZip敲除小鼠，使肖恩将获得经验， 组织学技术和先进的显微镜，以及分子分析， 生物信息学

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.