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：
9973121
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/9973121
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

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：癫痫病是一种复发性癫痫发作的疾病，影响了世界人口的1％。现在时间，我们对人脑区域如何变得癫痫病并产生癫痫发作的时间一无所知。我们也没有治愈或预防癫痫形成的药物，这是一种称为癫痫发生的过程。当前的药物可以抑制癫痫发作，但尚未证明可以预防或治愈该疾病，以便停止服用药物的癫痫患者继续癫痫发作。一种可以导致的方法癫痫发作的永久减少是癫痫手术，以去除癫痫发作的大脑局灶性区域。经常作为这些手术的一部分进行的长期颅内记录表明非常频繁经常在癫痫发作的大脑区域或附近的癫痫放电或“尖峰”，这表明这些 “泄露”（在癫痫发作之间）尖峰与癫痫大脑区域高度相关。实际上充出现在癫痫发生的一些动物模型中。但是，确切的关系发作的尖峰和癫痫发作尚不清楚，也不清楚是否阻塞癫痫发作的治疗方法阻止尖峰或反之亦然。在这里，我们计划扩展我们采取公正方法来识别新的治疗目标的工作基于来自精确局部人类新皮层区域的高吞吐基因组研究的癫痫接受癫痫手术的患者。我们将使用从基因表达研究中获取的数据人类癫痫大脑以识别与发发中心相关的基因和分子途径并进行比较这些脑区域会产生癫痫发作。我们还开发了一种新颖的计算方法区分组织区域的组织区域，其中发作的尖峰与散布的地方。空间特定细胞类型，基因和信号中间体的组织将映射到特定的层流区域以及最近发现的> micrersions =在更深的皮质层中仅存在于高尖峰中地区。最后，将间隔尖峰与癫痫发作分开的体内动物模型将用于测试 MAP激酶信号传导的特定功能在间隔峰值和癫痫发作中作为潜在的治疗剂癫痫发生并确定癫痫。