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Validation of a Novel Mouse Model of Temporal Lobe Epilepsy

颞叶癫痫新型小鼠模型的验证

基本信息

批准号：
10618726
负责人：
EDWARD PEREZ-REYES
金额：
$ 40.67万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10618726
关键词：
Address Adoption Affect Animal Model Animals Antiepileptic Agents Antiepileptogenic Appearance Biological Assay Brain region Caricatures Cell Death Cessation of life Clinical Clinical Trials Design Data Development Disease Drug Screening Electric Stimulation Electroconvulsive Shock Electroencephalography Enterobacteria phage P1 Cre recombinase Epilepsy Frequencies Functional disorder Funding Genes Goals Grant Hippocampus (Brain)Human Lead Link Medication Management Medicine Modeling Mouse Strains Mus National Institute of Neurological Disorders and Stroke Neurons Partial Epilepsies Patients Persons Pharmaceutical Preparations Pharmacology Phase Play Problem Solving Protocols documentation Rattus Research Rodent Running Sclerosis Seizures Severities Status Epilepticus Temporal Lobe Epilepsy Testing Tonic - clonic seizures United States National Institutes of Health Universities Utah Validation Virginia Work base cost drug discovery drug testing efficacy testing excitatory neuron experience hippocampal sclerosis human disease improved inhibitory neuron kainate mouse model neuron loss novel novel therapeutics process repeatability programs promoter screening screening program translational goal vesicular GABA transporter

项目摘要

Project summary The long-term goal of these studies is to develop novel therapeutics for epilepsy patients whose seizures are not well-controlled by current drugs (pharmacoresistant). Many of these patients have a type of focal epilepsy called temporal lobe epilepsy (TLE). There has been little progress in the development of novel therapies for these patients because of the lack of suitable animal models. Current TLE models show much greater neuronal death and hippocampal sclerosis than observed in patients, and a highly variable occurrence of seizures that precludes drug testing. The proposed studies will validate the usefulness of new mouse model of TLE that overcomes these problems. It was discovered that a mild kindling protocol of a specific strain of mice, VGAT- Cre, led to spontaneous seizures. Kindling refers to the process where repeated electrical stimulations eventually trigger tonic-clonic seizures. However, kindling only leads to spontaneous seizures in VGAT-Cre mice. These mice express Cre recombinase under the control of the vesicular GABA transporter (VGAT), a gene that is specifically expressed in GABAergic inhibitory neurons. Loss, or dysfunction, of these neurons in the hippocampus has been linked to the development of temporal lobe epilepsy. The first aim of this study will optimize kindling protocols to generate mice with an ideal frequency of spontaneous seizures for drug testing. The second aim is to validate that these mice respond to currently available antiseizure drugs. This work will be done by Dr. Wilcox’s group at the University of Utah, who also directs the NIH-sponsored Epilepsy Therapy Screening Program.

项目摘要这些研究的长期目标是为癫痫患者开发新的治疗方法，当前药物控制不佳（耐药性）。这些患者中的许多人患有一种局灶性癫痫颞叶癫痫（Temporal lobe epilepsy，TLE）在开发新的治疗方法方面进展甚微，这些患者由于缺乏合适的动物模型。目前的TLE模型显示，死亡和海马硬化，以及癫痫发作的高度可变性，排除了毒品测试所提出的研究将验证新的TLE小鼠模型的有用性，克服了这些问题。人们发现，一种特定品系的小鼠VGAT-1的轻度点燃方案，导致自发性癫痫发作。点燃是指反复的电刺激最终引发强直阵挛发作然而，点燃仅导致VGAT-Cre小鼠的自发性癫痫发作。这些小鼠在囊泡GABA转运蛋白（VGAT）的控制下表达Cre重组酶，VGAT是一种基因，特异性表达于GABA能抑制性神经元。这些神经元的丢失或功能障碍，海马体与颞叶癫痫的发展有关。本研究的第一个目的是优化点燃方案，以产生具有理想自发癫痫发作频率的小鼠用于药物测试。第二个目的是验证这些小鼠对目前可用的抗癫痫药物的反应。这项工作将这项研究是由犹他州大学的威尔科克斯博士的小组完成的，他也是NIH赞助的癫痫治疗的指导者筛选程序。