Molecular and Cellular Basis of Spiking and Seizures in Neocortical Epilepsy

新皮质癫痫发作和癫痫发作的分子和细胞基础

• 批准号: 9816309
• 负责人: JEFFREY A LOEB
• 金额: $ 45.75万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816309
• 关键词: Address; Affect; Algorithms; Animal Model; Animals; Anticonvulsants; Antiepileptogenic; Back; Biological Markers; Brain; Brain region; CREB1 gene; Cells; Chronic; Clinical; Data; Development; Disease; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Gene Chips; Gene Cluster; Gene Expression; Genes; Genomics; Histologic; Histology; Human; In Situ Hybridization; Injections; Lead; Link; MAP Kinase Gene; MEK inhibition; MEKs; Maps; Measures; Microglia; Mitogen-Activated Protein Kinases; Molecular; Monitor; Motor Cortex; Neocortex; Neurons; Operative Surgical Procedures; Pathway interactions; Patient Care; Patients; Pattern; Pharmaceutical Preparations; Population; Process; Rattus; Recurrent disease; Role; Sampling; Seizures; Signal Pathway; Signal Transduction; Site; Somatosensory Cortex; Spatial Distribution; Stains; Synapses; Testing; Tetanus Toxin; Therapeutic; Time; Tissue Differentiation; Tissues; Translating; Validation; Western Blotting; Work; base; brain abnormalities; cell type; differential expression; functional genomics; genomic data; human tissue; in vivo; inhibitor/antagonist; neocortical; new therapeutic target; novel; prevent; signal processing; spatial relationship; transcriptome sequencing; validation studies

Summary: Epilepsy is a disease of recurrent seizures that affects up to 1% of the world's population. At present time, we understand very little about how regions of the human brain become epileptic and produce seizures. We also have no medications that cure or prevent epilepsy from forming, a process known as epileptogenesis. Current medications can suppress seizures, but have not been shown to prevent or cure the disease, so that epileptic patients who stop taking their medications continue to have seizures. One approach that can lead to a permanent reduction in seizures is epilepsy surgery to remove focal regions of the brain where seizures start. Long term intracranial recordings that are often performed as part of these surgeries reveal extremely frequent epileptic discharges or 'spikes' often at or near regions of the brain where seizures start, suggesting that these 'interictal' (between seizures) spikes are highly associated with epileptic brain regions. In fact interictal spikes appear before seizures in some animal models of epileptogenesis. However, the exact relationship between interictal spiking and seizures is not known nor is it clear whether treatments that block seizures block spiking or vice versa. Here, we plan to extend our work that has taken an unbiased approach to identify new therapeutic targets for epilepsy based on high throughput genomic studies from precisely localized human neocortical regions from patients who have undergone epilepsy surgery. We will use data acquired from gene expression studies in human epileptic brain to identify genes and molecular pathways associated with interictal spiking and compare these to brain regions that produce seizures. We have also developed a novel computational approach to differentiate tissue regions where interictal spiking is generated versus where it spreads. The spatial organization of specific cell types, genes, and signaling intermediates will be mapped to specific laminar regions as well as to recently discovered >microlesions= in deeper cortical layers that are present only in high spiking regions. Finally, an in vivo animal model that separates interictal spiking from seizures will be used to test the specific functions of MAP Kinase signaling on interictal spiking and seizures as potential therapeutics for both epileptogenesis and established epilepsy.

总结： 癫痫是一种反复发作的疾病，影响世界人口的1%。目前 然而，我们对人类大脑的某些区域是如何变得癫痫并引起癫痫发作的了解很少。 我们也没有治疗或预防癫痫形成的药物，这一过程被称为癫痫发生。 目前的药物可以抑制癫痫发作，但尚未显示出预防或治愈疾病，因此， 停止服药的癫痫患者继续癫痫发作。一种方法可以导致 癫痫发作的永久性减少是癫痫手术，以去除癫痫发作开始的大脑病灶区域。 作为这些手术的一部分，经常进行的长期颅内记录显示， 癫痫放电或“尖峰”往往在或接近癫痫发作开始的大脑区域，这表明这些 “发作间期”（发作之间）尖峰与癫痫脑区高度相关。事实上， 在某些癫痫发生的动物模型中出现在癫痫发作之前。然而， 发作间期尖峰和癫痫发作尚不清楚，也不清楚阻断癫痫发作的治疗是否阻断尖峰或 反之亦然 在这里，我们计划扩展我们的工作，采取了公正的方法来确定新的治疗靶点 基于从精确定位的人类新皮层区域进行的高通量基因组研究， 接受过癫痫手术的患者。我们将使用从基因表达研究中获得的数据， 人类癫痫脑中与发作间期峰电位相关基因和分子通路的鉴定和比较 这些神经元会进入大脑中导致癫痫发作的区域。我们还开发了一种新的计算方法， 区分发作间期尖峰产生的组织区域与其扩散的组织区域。空间 特定细胞类型、基因和信号中间体的组织将被映射到特定的层区域 以及最近发现的>微病变=仅在高峰值中存在的更深皮质层中 地区最后，将使用将发作间期尖峰与癫痫发作分开的体内动物模型来测试本发明。 MAP激酶信号传导在发作间期峰化和癫痫发作中的特异性功能，作为两者的潜在治疗剂 癫痫发生和已确定的癫痫。