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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

基本信息

批准号：
10376208
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
项目类别：
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/10376208
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 antagonist base brain abnormalities cell type differential expression functional genomics genomic data human tissue in vivo inhibitor neocortical new therapeutic target novel prevent signal processing spatial relationship transcriptome sequencing validation studies

项目摘要

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.

摘要：癫痫是一种反复发作的疾病，影响着多达1%的世界人口。目前随着时间的推移，我们对人类大脑的某些区域是如何癫痫发作并产生癫痫发作知之甚少。我们也没有治愈或防止癫痫形成的药物，这一过程被称为癫痫发生。目前的药物可以抑制癫痫发作，但尚未被证明能预防或治愈这种疾病，因此停止服药的癫痫患者会继续癫痫发作。一种方法可以导致永久性减少癫痫发作的方法是癫痫手术，移除大脑中癫痫发作开始的局部区域。作为这些手术的一部分，经常进行的长期颅内记录显示非常频繁癫痫样放电或“尖峰”经常出现在癫痫发作开始的大脑区域或附近，这表明这些发作间歇期(发作间歇期)的棘波与癫痫的脑区高度相关。事实上，发作间期尖峰在某些癫痫发生的动物模型中出现在癫痫发作之前。然而，两者之间的确切关系发作间期的尖峰电位和癫痫发作尚不清楚，也不清楚阻断癫痫发作的治疗方法是否能阻断尖峰电位或反之亦然。在这里，我们计划扩大我们的工作，采取公正的方法来确定新的治疗靶点基于来自精确定位的人类新皮质区域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内与发作间期放电相关基因和分子通路的识别与比较这些神经传导到产生癫痫发作的大脑区域。我们还开发了一种新的计算方法来区分发作间期棘波产生的组织区域和其扩散的区域。空间上的特定细胞类型、基因和信号中间产物的组织将被映射到特定的板层区域以及最近发现的仅存在于高峰期的更深皮质层的微小病变地区。最后，一个分离发作间期尖峰电位和癫痫发作的体内动物模型将被用来测试 MAP激酶信号在发作间期放电和癫痫发作中的特殊作用癫痫的发生和确定的癫痫。