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：
10613487
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613487
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 Lesion 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 biomarker identification 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.

概括：癫痫是一种反复发作的疾病，影响着世界上多达 1% 的人口。现在当时，我们对人脑区域如何变得癫痫并产生癫痫发作知之甚少。我们也没有药物可以治愈或预防癫痫的形成，这一过程称为癫痫发生。目前的药物可以抑制癫痫发作，但尚未被证明可以预防或治愈该疾病，因此停止服药的癫痫患者仍会出现癫痫发作。一种方法可以导致永久减少癫痫发作是通过癫痫手术去除癫痫发作开始的大脑局部区域。通常作为这些手术的一部分进行的长期颅内记录显示极其频繁癫痫放电或“尖峰”通常出现在癫痫发作开始的大脑区域或附近，这表明这些 “发作间期”（癫痫发作之间）尖峰与癫痫大脑区域高度相关。事实上，发作间期尖峰在一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尖峰和癫痫发作尚不清楚，也不清楚阻止癫痫发作的治疗是否会阻止尖峰或癫痫发作。反之亦然。在这里，我们计划扩展我们的工作，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，用于癫痫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大脑识别与发作间期尖峰相关的基因和分子途径并进行比较这些会影响产生癫痫发作的大脑区域。我们还开发了一种新颖的计算方法区分发作间期尖峰产生的组织区域和扩散的组织区域。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状区域以及最近在更深的皮质层中发现的>微损伤=仅存在于高尖峰中地区。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 MAP 激酶信号传导对发作间期尖峰和癫痫发作的特定功能作为两者的潜在治疗方法癫痫发生和确立的癫痫。